TW202045153A

TW202045153A - Minimizing agglomeration, aeration, and preserving the coating of pharmaceutical compositions comprising ibuprofen

Info

Publication number: TW202045153A
Application number: TW109105773A
Authority: TW
Inventors: 羅莎琳麥克勞林; 亞當帕克; 西曼安德魯馬丁哈瓦仕; 喬納森懷特豪斯; 克雷格偉頓
Original assignee: 英商康泰倫特英國斯文敦載迪斯有限公司
Priority date: 2019-02-22
Filing date: 2020-02-21
Publication date: 2020-12-16
Also published as: US11931464B2; GB2597577A; KR20210129649A; GB2597577B; BR112021016421A2; HUE064472T2; IL285653A; SG11202108690YA; GB2585414A; US20200390716A1; GB202002484D0; ES2966816T3; EP4282409A3; US11166919B2; US11077067B2; WO2020169989A1; PL3927312T3; EP4282409A2; EP3927312C0; CA3129395A1

Abstract

Provided are pharmaceutical compositions and methods for preparing pharmaceutical compositions comprising Ibuprofen using solventless mixing methods. Excess coating material that is not bound to coated Ibuprofen may be removed by a sieving process. Coating and dosing ratios can also be optimized to minimize the amount of excess unbound coating material. Additionally, the compositions can be formulated to preserve the functional coating of coated Ibuprofen and to minimize aeration of Ibuprofen when mixed into suspension.

Description

含伊布洛芬之醫藥組合物之塗層之黏聚最小化、通氣及保存Minimization of adhesion, ventilation and preservation of coatings of pharmaceutical compositions containing ibuprofen

本發明係關於塗覆伊布洛芬之方法，且更具體而言係關於將過量塗覆材料最小化以防止在儲存期間凍乾之經口崩解劑型中的經塗覆之伊布洛芬(Ibuprofen)黏聚的方法、將包含伊布洛芬之醫藥懸浮液的通氣最小化以改良計量重量準確度同時維持伊布洛芬上之功能性塗層之完整性的方法、及保存以無溶劑混合方法製備且經調配以在經口投與時延遲伊布洛芬之釋放之經塗覆之伊布洛芬的方法。The present invention relates to a method of applying ibuprofen, and more specifically to minimizing excess coating material to prevent coated ibuprofen in an orally disintegrating dosage form that is freeze-dried during storage (Ibuprofen) a method of cohesion, a method of minimizing the ventilation of a pharmaceutical suspension containing Ibuprofen to improve the accuracy of metering weight while maintaining the integrity of the functional coating on Ibuprofen, and a method of preservation The solvent mixing method is a method of preparing and formulating coated ibuprofen to delay the release of ibuprofen during oral administration.

醫藥組合物通常包括活性醫藥成份以及一或多種非活性成份二者。活性醫藥成份(API)具有生物活性且經設計以直接影響患者之症狀、疾病、病症及/或病痛。活性醫藥成份之一個實例係伊布洛芬。另一方面，醫藥組合物之非活性成份係醫藥惰性的且可用於各種目的，包括但不限於改良長期穩定性、填充或稀釋固體調配物、促進藥物吸收、調節液體調配物之黏度、增強溶解度及/或有助於醫藥組合物之製造。Pharmaceutical compositions generally include both active pharmaceutical ingredients and one or more inactive ingredients. Active pharmaceutical ingredients (API) have biological activity and are designed to directly affect the patient's symptoms, diseases, disorders, and/or pain. An example of an active pharmaceutical ingredient is ibuprofen. On the other hand, the inactive ingredients of the pharmaceutical composition are pharmaceutical inert and can be used for various purposes, including but not limited to improving long-term stability, filling or diluting solid formulations, promoting drug absorption, adjusting the viscosity of liquid formulations, and enhancing solubility And/or contribute to the manufacture of pharmaceutical compositions.

另外，一些非活性成份可用於掩蔽API (例如伊布洛芬)之味道。已知許多API若允許在口腔中溶解會展現令人不愉快之感官性質，例如苦味、燒灼感及麻木。舉例而言，一些經口投與之醫藥組合物經設計以分散於口中以能夠在無水之情況下投與，且靶向兒科患者、老年患者、動物患者及/或可具有吞嚥困難之其他類型之患者。對於該等類型之經口投與之醫藥組合物，可使用非活性成份形成「功能性塗層」以掩蔽API或伊布洛芬之味道。In addition, some inactive ingredients can be used to mask the taste of API (such as Ibuprofen). Many APIs are known to exhibit unpleasant organoleptic properties such as bitterness, burning sensation and numbness if allowed to dissolve in the oral cavity. For example, some oral administration and pharmaceutical compositions are designed to be dispersed in the mouth so that they can be administered without water, and are targeted at pediatric patients, elderly patients, animal patients, and/or other types that may have dysphagia The patient. For these types of pharmaceutical compositions for oral administration, inactive ingredients can be used to form a "functional coating" to mask the taste of API or Ibuprofen.

舉例而言，非活性成份可用於藉由濕塗覆或乾塗覆API顆粒以產生包圍API顆粒之功能性塗層、從而防止API在口中釋放來掩蔽API之味道。在濕顆粒塗覆中，將非活性成份(聚合物及添加劑)溶解或分散於溶劑或水中以形成懸浮液或溶液。然後可將此懸浮液或溶液噴霧至API顆粒之表面上，以藉由溶劑或水之蒸發而形成膜之塗層。濕顆粒塗覆技術之實例包括微囊化、流化床塗覆、噴霧乾燥、鍋塗覆等。在乾顆粒塗覆(亦稱為無溶劑塗覆)中，API顆粒用非活性成份(聚合物及添加劑)之細顆粒物理塗覆以形成顆粒複合物。乾顆粒塗覆之實例包括熱熔融塗覆、超臨界塗覆、壓緊塗覆、靜電塗覆。用掩味非活性成份塗覆之API顆粒可為具有吞嚥困難或對原本將導致負面患者體驗及差的依從性之味道敏感的患者提供更令人愉快之體驗。For example, inactive ingredients can be used to wet or dry coat the API particles to produce a functional coating surrounding the API particles, thereby preventing the release of the API in the mouth to mask the taste of the API. In wet particle coating, inactive ingredients (polymers and additives) are dissolved or dispersed in a solvent or water to form a suspension or solution. This suspension or solution can then be sprayed onto the surface of API particles to form a coating of the film by evaporation of the solvent or water. Examples of wet particle coating techniques include microencapsulation, fluidized bed coating, spray drying, pan coating and the like. In dry particle coating (also called solventless coating), API particles are physically coated with fine particles of inactive ingredients (polymers and additives) to form particle composites. Examples of dry particle coating include hot melt coating, supercritical coating, compression coating, and electrostatic coating. API particles coated with taste-masking inactive ingredients can provide a more pleasant experience for patients who have difficulty swallowing or are sensitive to tastes that would otherwise lead to negative patient experience and poor compliance.

另外，一種類型之醫藥組合物係經口崩解錠劑(ODT)。ODT係靶向兒科患者、老年患者、動物患者及/或可具有吞嚥困難之其他類型之患者的醫藥組合物。In addition, one type of pharmaceutical composition is an orally disintegrating tablet (ODT). ODT is a pharmaceutical composition targeted at pediatric patients, elderly patients, animal patients, and/or other types of patients who may have difficulty swallowing.

為了將醫藥組合物準確地分配成小的可投與形式，可將疏水性經塗覆之API顆粒置於基質溶液/懸浮液中以形成醫藥懸浮液。混合形成醫藥懸浮液允許改良計量準確度。通常，可將包含疏水性經塗覆之API顆粒之此醫藥懸浮液計量至模具中，乾燥，且然後可將經模製物品轉移至(例如)瓶中。然而，醫藥組合物之此種處理可增加諸如損害及污染等風險。In order to accurately dispense the pharmaceutical composition into small administrable forms, the hydrophobic coated API particles can be placed in a matrix solution/suspension to form a pharmaceutical suspension. The mixing to form a pharmaceutical suspension allows for improved metering accuracy. Generally, this pharmaceutical suspension containing hydrophobic coated API particles can be metered into a mold, dried, and then the molded article can be transferred to, for example, a bottle. However, such treatment of pharmaceutical compositions can increase risks such as damage and contamination.

因此，相反，當今將許多API懸浮液計量至預成型泡罩包中。預成型泡罩包消除上述處理步驟之一。代替定量加入模具中且然後將經模製物品轉移至瓶中進行包裝，預成型泡罩包允許製造商將醫藥懸浮液計量至預成型泡罩包中，該預成型泡罩包可經乾燥，然後密封及包裝。因此，預成型泡罩包既用作模具，亦用作可儲存醫藥組合物之包裝。Therefore, on the contrary, many API suspensions are metered into preformed blister packs today. The pre-formed blister pack eliminates one of the above processing steps. Instead of metering into the mold and then transferring the molded article to a bottle for packaging, the pre-formed blister pack allows the manufacturer to meter the pharmaceutical suspension into a pre-formed blister pack, which can be dried, Then seal and package. Therefore, the pre-formed blister pack is used both as a mold and as a packaging for storing pharmaceutical compositions.

提供使用各種混合方法製備之用於經塗覆之伊布洛芬之塗覆材料之黏聚最小化的方法。塗覆材料之黏聚可降低醫藥產品隨時間之穩定性。舉例而言，若藥物產品包含黏聚之塗覆材料，則其崩解時間可隨時間而增加。增加之崩解時間及/或降低之溶解速率暗指不穩定之醫藥產品。不穩定之醫藥產品可導致比期望更短之儲放壽命。因此，所提供之實施例可有助於使經塗覆之伊布洛芬之塗覆材料之黏聚最小化，以改良醫藥產品在儲存期間之穩定性並增加其儲放壽命。Provide methods for minimizing the cohesion of coating materials for coated Ibuprofen prepared using various mixing methods. Cohesion of the coating material can reduce the stability of the pharmaceutical product over time. For example, if the drug product contains a cohesive coating material, its disintegration time can increase over time. Increased disintegration time and/or decreased dissolution rate allude to unstable pharmaceutical products. Unstable pharmaceutical products can lead to a shorter storage life than expected. Therefore, the provided embodiments can help minimize the cohesion of the coating material of the coated ibprofen, so as to improve the stability of the medical product during storage and increase its storage life.

舉例而言，所述方法包括自經塗覆之伊布洛芬去除過量塗覆材料，以使塗覆材料顆粒黏聚之可能性最小化。具體而言，提供之方法包括篩分經塗覆之伊布洛芬，使得最終醫藥產品由乾基質充分包圍，從而使塗覆材料顆粒在儲存時之任何黏聚最小化。所述醫藥組合物提供隨時間保持相對穩定之崩解時間及溶解速率。For example, the method includes removing excess coating material from the coated ibuprofen to minimize the possibility of coating material particles agglomerating. Specifically, the method provided includes sieving the coated ibuprofen so that the final medical product is sufficiently surrounded by a dry matrix, thereby minimizing any agglomeration of the coated material particles during storage. The pharmaceutical composition provides a relatively stable disintegration time and dissolution rate over time.

亦提供可使懸浮液中疏水性經塗覆之伊布洛芬之通氣最小化的組合物及製備組合物之方法。舉例而言，疏水性經塗覆之伊布洛芬可混合至基質溶液/懸浮液中以形成醫藥懸浮液，以準確地計量至模具中以形成用於投與給患者之固體醫藥組合物(例如，物品、錠劑等)。然而，經塗覆之伊布洛芬之疏水性導致經塗覆之伊布洛芬抵抗分散至溶液/懸浮液中。因此，此可導致空氣被醫藥懸浮液夾帶，亦稱為通氣。醫藥懸浮液夾帶之空氣或通氣可引起醫藥懸浮液中經塗覆之伊布洛芬之相分離，從而導致醫藥懸浮液不均質。通氣及不均質之醫藥懸浮液可導致計量至預成型泡罩包之包含疏水性伊布洛芬之醫藥懸浮液的計量重量準確度差，且在成品(即醫藥組合物)中之含量均勻性差。It also provides a composition that minimizes the ventilation of hydrophobic coated ibuprofen in the suspension and a method for preparing the composition. For example, the hydrophobic coated ibuprofen can be mixed into a matrix solution/suspension to form a pharmaceutical suspension to be accurately metered into a mold to form a solid pharmaceutical composition for administration to a patient ( For example, articles, lozenges, etc.). However, the hydrophobicity of the coated ibuprofen causes the coated ibuprofen to resist dispersion into the solution/suspension. Therefore, this can cause air to be entrained by the pharmaceutical suspension, also known as ventilation. The air or ventilation entrained in the pharmaceutical suspension can cause the phase separation of the coated ibuprofen in the pharmaceutical suspension, thereby causing the pharmaceutical suspension to be inhomogeneous. Ventilated and heterogeneous pharmaceutical suspensions can lead to poor measurement accuracy of the pharmaceutical suspensions containing hydrophobic ibuprofen measured into the preformed blister packs, and poor content uniformity in the finished product (ie, pharmaceutical composition) .

由於醫藥懸浮液之高黏度，防通氣及/或最小化通氣之傳統機械方式尚未發現有成功的。舉例而言，藉由對醫藥懸浮液施加真空可實現通氣最小化，但端視組成及進一步處理要求而定，此方法可能係不適宜的。具體而言，對醫藥懸浮液施加真空可引起懸浮液上升，此乃因黏性懸浮液「抓握」在夾帶之空氣上。揮發性調配物組分亦可在真空處理期間損失。此外，傳統防通氣劑(例如乙醇或西甲矽油乳液)類似地不能有效地對懸浮液防通氣。Due to the high viscosity of pharmaceutical suspensions, traditional mechanical methods for preventing ventilation and/or minimizing ventilation have not been found to be successful. For example, ventilation can be minimized by applying a vacuum to the pharmaceutical suspension, but depending on the composition and further processing requirements, this method may be unsuitable. Specifically, applying a vacuum to the pharmaceutical suspension can cause the suspension to rise, because the viscous suspension "grabs" on the entrained air. Volatile formulation components can also be lost during vacuum processing. In addition, traditional anti-aeration agents (such as ethanol or simethicone emulsion) similarly cannot effectively prevent aeration of suspensions.

因此，本文提供之組合物及方法使包含疏水性經塗覆之伊布洛芬之醫藥懸浮液之通氣最小化，以改良懸浮液之均質性並增加計量重量準確度。具體地，提供之實施例可包括包含含有萜烯及/或萜品醇之化學化合物的基質溶液/懸浮液。在一些實施例中，基質溶液/懸浮液可包含萜烯檸檬烯。藉由引入包含萜烯烯之化學化合物(例如檸檬烯)，疏水性經塗覆之伊布洛芬可更容易地併入基質溶液/懸浮液中，從而使醫藥懸浮液之總體通氣最小化。Therefore, the compositions and methods provided herein minimize the aeration of pharmaceutical suspensions containing hydrophobic coated ibuprofen to improve the homogeneity of the suspension and increase the accuracy of metering weight. Specifically, the provided embodiment may include a matrix solution/suspension containing a chemical compound containing terpene and/or terpineol. In some embodiments, the matrix solution/suspension may include the terpene limonene. By introducing terpene-containing chemical compounds (such as limonene), the hydrophobic coated ibuprofen can be more easily incorporated into the matrix solution/suspension, thereby minimizing the overall aeration of the pharmaceutical suspension.

本文亦提供醫藥組合物及製備醫藥組合物之方法，該等醫藥組合物經調配以在製造過程期間保存功能性塗覆之伊布洛芬之功能性塗層。通常混合功能性塗覆之伊布洛芬以形成醫藥懸浮液。醫藥懸浮液允許準確計量以形成可投與之醫藥產品。通常，將功能性塗覆之伊布洛芬併入醫藥懸浮液中所需之剪切力可引起功能性塗層被侵蝕。此塗層之侵蝕可破壞或損害功能性塗層之性質。因此，當經口投與給患者時，具有侵蝕之塗層之功能性塗覆之伊布洛芬可經歷增加之溶解速率及降低之掩味性質。Also provided herein are pharmaceutical compositions and methods for preparing pharmaceutical compositions that are formulated to preserve the functional coating of functionally coated ibuprofen during the manufacturing process. The functionally coated ibuprofen is usually mixed to form a pharmaceutical suspension. Pharmaceutical suspensions allow accurate metering to form pharmaceutical products that can be administered. Generally, the shear force required to incorporate the functionally coated ibuprofen into the pharmaceutical suspension can cause the functional coating to be corroded. The erosion of this coating can destroy or impair the properties of the functional coating. Therefore, when administered orally to a patient, functionally coated ibuprofen with an eroding coating can experience increased dissolution rate and decreased taste masking properties.

然而，本文提供之醫藥組合物及製備醫藥組合物之方法包括用疏水性發煙二氧化矽保存醫藥懸浮液中之功能性塗覆之伊布洛芬的塗層。具體地，疏水性發煙二氧化矽可提供包圍功能性塗覆之伊布洛芬顆粒及/或包埋於其中之保護層。在一些實施例中，產生功能性塗覆之伊布洛芬之無溶劑方法可產生包含第一塗層之伊布洛芬。根據一些實施例，可在無溶劑混合過程期間添加疏水性發煙二氧化矽以產生包圍功能性塗覆之伊布洛芬及/或部分或完全包埋於其中之第二保護性塗層。However, the pharmaceutical composition provided herein and the method for preparing the pharmaceutical composition include the preservation of the functionally coated ibuprofen coating in the pharmaceutical suspension with hydrophobic fuming silica. Specifically, the hydrophobic fuming silica can provide a protective layer surrounding and/or embedding the functionally coated ibuprofen particles. In some embodiments, a solvent-free method of producing functionally coated ibuprofen can produce ibuprofen including the first coating. According to some embodiments, the hydrophobic fuming silica may be added during the solvent-free mixing process to produce a second protective coating that surrounds the functional coating of ibuprofen and/or is partially or completely embedded therein.

另外，第二保護性塗層可限制功能性塗覆之伊布洛芬與基質溶液/懸浮液之間之相互作用，使得功能性塗覆之伊布洛芬對基質之性能特徵的影響最小化。In addition, the second protective coating can limit the interaction between the functionally coated Ibuprofen and the substrate solution/suspension, so that the functionally coated Ibuprofen can minimize the impact of the performance characteristics of the substrate .

在一些實施例中，醫藥組合物包含：65-85 % w/w伊布洛芬；15-30 % w/w塗覆伊布洛芬之塗覆材料；及3-15 % w/w包圍伊布洛芬之基質。在一些實施例中，醫藥組合物包含50-400 mg伊布洛芬。在一些實施例中，塗覆材料包含第一塗覆材料及第二塗覆材料且醫藥組合物包含10-30 % w/w第一塗覆材料及0.5-10 % w/w第二塗覆材料。在一些實施例中，第一塗覆材料包含蠟。在一些實施例中，第二塗覆材料包含二氧化矽。在一些實施例中，醫藥組合物包含1-5% w/w防通氣劑。在一些實施例中，第一塗覆材料包含巴西棕櫚蠟、合成蠟或小燭樹蠟中之一或多者。在一些實施例中，基質包含基質形成劑及結構形成劑。在一些實施例中，基質形成劑包含水溶性材料、水可分散材料、多肽、多醣、聚乙烯醇、聚乙烯基吡咯啶酮及***樹膠中之一或多者。在一些實施例中，基質形成劑包含多肽。在一些實施例中，多肽包含凝膠。在一些實施例中，結構形成劑包含甘露醇、右旋糖、乳糖、半乳糖及環糊精中之一或多者。在一些實施例中，結構形成劑包含甘露醇。在一些實施例中，醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。在一些實施例中，醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。在一些實施例中，醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有3秒或更少之崩解時間達至少兩個月。在一些實施例中，醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。在一些實施例中，醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。在一些實施例中，醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。在一些實施例中，醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。在一些實施例中，醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。在一些實施例中，醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。在一些實施例中，醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。在一些實施例中，醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。在一些實施例中，醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。在一些實施例中，醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。在一些實施例中，醫藥組合物在5分鐘後具有10%、5%、3%或更少之溶解測試結果。在一些實施例中，基質包含黏度調節劑。在一些實施例中，黏度調節劑包含黃原膠。在一些實施例中，防通氣劑包含萜烯或萜品醇中之一或多者。在一些實施例中，防通氣劑包含液體矯味劑。在一些實施例中，其中防通氣劑包含含有檸檬烯之液體矯味劑。在一些實施例中，防通氣劑包含橙味矯味劑、檸檬味矯味劑、葡萄柚味矯味劑、酸檸檬味矯味劑、草莓味矯味劑或薄荷味矯味劑中之一或多者。在一些實施例中，醫藥組合物包含3-10% w/w基質形成劑。在一些實施例中，醫藥組合物包含3-10 % w/w結構形成劑。In some embodiments, the pharmaceutical composition comprises: 65-85% w/w ibuprofen; 15-30% w/w coating material for ibuprofen; and 3-15% w/w surrounding The substrate of Ibuprofen. In some embodiments, the pharmaceutical composition comprises 50-400 mg ibuprofen. In some embodiments, the coating material includes a first coating material and a second coating material, and the pharmaceutical composition includes 10-30% w/w first coating material and 0.5-10% w/w second coating material. In some embodiments, the first coating material includes wax. In some embodiments, the second coating material includes silicon dioxide. In some embodiments, the pharmaceutical composition comprises 1-5% w/w anti-ventilation agent. In some embodiments, the first coating material includes one or more of carnauba wax, synthetic wax, or candelilla wax. In some embodiments, the matrix includes a matrix forming agent and a structure forming agent. In some embodiments, the matrix forming agent includes one or more of water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic. In some embodiments, the matrix forming agent comprises a polypeptide. In some embodiments, the polypeptide comprises a gel. In some embodiments, the structure forming agent includes one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments, the structure forming agent comprises mannitol. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25° C. and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25° C. and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40° C. and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40° C. and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25° C. and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25° C. and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a dissolution test result of 10%, 5%, 3% or less after 5 minutes. In some embodiments, the matrix includes a viscosity modifier. In some embodiments, the viscosity modifier comprises xanthan gum. In some embodiments, the anti-ventilation agent comprises one or more of terpenes or terpineol. In some embodiments, the anti-ventilation agent comprises a liquid flavoring agent. In some embodiments, the anti-ventilation agent includes a liquid flavoring agent containing limonene. In some embodiments, the anti-ventilation agent includes one or more of an orange flavor, a lemon flavor, a grapefruit flavor, a sour lemon flavor, a strawberry flavor, or a mint flavor. In some embodiments, the pharmaceutical composition comprises 3-10% w/w matrix former. In some embodiments, the pharmaceutical composition contains 3-10% w/w structure former.

在一些實施例中，可藉由包含以下步驟之方法製備醫藥組合物：用第一塗覆材料塗覆伊布洛芬以形成經塗覆之伊布洛芬，其中第一塗覆材料包含一或多種可變形組分；對經塗覆之伊布洛芬施加機械應力以使一或多種可變形組分變形；用包含二氧化矽之第二塗覆材料塗覆經塗覆之伊布洛芬；施加機械應力以將第二塗覆材料包埋至經塗覆之伊布洛芬之第一塗覆材料上；篩分經塗覆之伊布洛芬以去除過量第一塗覆材料，其中過量第一塗覆材料包含未結合至經塗覆之伊布洛芬之第一塗覆材料；形成包含兩次塗覆之伊布洛芬及基質溶液或懸浮液的醫藥懸浮液；將醫藥懸浮液計量至模具中；及冷凍乾燥模具中之經計量之醫藥懸浮液以形成醫藥組合物。在一些實施例中，篩分經塗覆之伊布洛芬包含使經塗覆之伊布洛芬通過包含兩個或更多個篩之裝置。在一些實施例中，篩分經塗覆之伊布洛芬包含將經塗覆之伊布洛芬篩分成75 µm或更大之平均粒度。在一些實施例中，篩分經塗覆之伊布洛芬包含將經塗覆之伊布洛芬篩分成200 µm或更小之平均粒度。在一些實施例中，經計量之醫藥懸浮液之重量在靶計量重量之10%內。在一些實施例中，經計量之醫藥懸浮液之重量具有在靶計量重量之5%內的一致性。在一些實施例中，經計量之醫藥懸浮液之重量具有在靶計量重量之2.5%內的一致性。在一些實施例中，經計量之醫藥懸浮液之重量具有在靶計量重量之1%內的一致性。在一些實施例中，將經塗覆之伊布洛芬混合至基質溶液或懸浮液中包含在15-20℃下線上混合。在一些實施例中，經塗覆之伊布洛芬在混合至溶液基質中之後的前2個小時內經歷小於40%之粒度損失。在一些實施例中，經塗覆之伊布洛芬在混合至溶液基質中之後的前2個小時內經歷小於30%之粒度損失。在一些實施例中，經塗覆之伊布洛芬在混合至溶液基質中之後的前2個小時內經歷小於20%之粒度損失。In some embodiments, the pharmaceutical composition may be prepared by a method including the following steps: coating ibuprofen with a first coating material to form a coated ibuprofen, wherein the first coating material includes a Or more deformable components; applying mechanical stress to the coated ibprofen to deform one or more deformable components; coating the coated ibprofen with a second coating material containing silicon dioxide Fen; applying mechanical stress to embed the second coating material on the first coating material of coated ibuprofen; sieving the coated ibuprofen to remove excess first coating material, Wherein the excess of the first coating material includes the first coating material that is not bound to the coated ibuprofen; forming a pharmaceutical suspension containing the twice-coated ibuprofen and the matrix solution or suspension; the medicine The suspension is metered into the mold; and the metered pharmaceutical suspension in the mold is freeze-dried to form a pharmaceutical composition. In some embodiments, sieving the coated ibuprofen comprises passing the coated ibuprofen through a device comprising two or more screens. In some embodiments, sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 75 µm or greater. In some embodiments, sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 200 µm or less. In some embodiments, the weight of the metered pharmaceutical suspension is within 10% of the target metered weight. In some embodiments, the weight of the metered pharmaceutical suspension has a consistency within 5% of the target metered weight. In some embodiments, the weight of the metered pharmaceutical suspension has a consistency within 2.5% of the target metered weight. In some embodiments, the weight of the metered pharmaceutical suspension has a consistency within 1% of the target metered weight. In some embodiments, mixing the coated ibuprofen into the matrix solution or suspension includes in-line mixing at 15-20°C. In some embodiments, the coated ibuprofen experiences a particle size loss of less than 40% within the first 2 hours after mixing into the solution matrix. In some embodiments, the coated ibuprofen experiences a particle size loss of less than 30% in the first 2 hours after mixing into the solution matrix. In some embodiments, the coated ibuprofen experiences a particle size loss of less than 20% within the first 2 hours after mixing into the solution matrix.

在一些實施例中，治療患者之方法包含向患者投與本文揭示之任一者之醫藥組合物。在一些實施例中，患者係人類。In some embodiments, a method of treating a patient comprises administering to the patient a pharmaceutical composition of any of the disclosed herein. In some embodiments, the patient is a human.

在一些實施例中，製備醫藥組合物之方法包含：用第一塗覆材料塗覆伊布洛芬以形成經塗覆之伊布洛芬，其中第一塗覆材料包含一或多種可變形組分；對經塗覆之伊布洛芬施加機械應力以使一或多種可變形組分變形；用包含二氧化矽之第二塗覆材料塗覆經塗覆之伊布洛芬；施加機械應力以將第二塗覆材料包埋至經塗覆之伊布洛芬之第一塗覆材料上；篩分經塗覆之伊布洛芬以去除過量第一塗覆材料，其中過量第一塗覆材料包含未結合至經塗覆之伊布洛芬之第一塗覆材料；形成包含兩次塗覆之伊布洛芬及基質溶液或懸浮液的醫藥懸浮液；將醫藥懸浮液計量至模具中；及冷凍乾燥模具中之經計量之醫藥懸浮液以形成醫藥組合物。In some embodiments, the method of preparing the pharmaceutical composition comprises: coating ibuprofen with a first coating material to form a coated ibuprofen, wherein the first coating material includes one or more deformable groups Points; apply mechanical stress to the coated ibuprofen to deform one or more deformable components; coat the coated ibuprofen with a second coating material containing silicon dioxide; apply mechanical stress To embed the second coating material on the first coating material of the coated ibuprofen; sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating The coating material includes a first coating material that is not bound to the coated ibuprofen; forming a pharmaceutical suspension containing twice-coated ibuprofen and a matrix solution or suspension; metering the pharmaceutical suspension into the mold Medium; and freeze-dry the metered pharmaceutical suspension in the mold to form a pharmaceutical composition.

相關申請案之交叉參考Cross reference of related applications

本申請案主張美國臨時申請案第62/809,307號、第62/809,287號及第62/809,293號之優先權，其各自於2019年2月22日提出申請，其各自全部內容以引用方式併入本文中。This application claims the priority of U.S. Provisional Application Nos. 62/809,307, 62/809,287 and 62/809,293, each of which filed an application on February 22, 2019, and the entire contents of each are incorporated by reference In this article.

本文闡述最小化及/或防止經塗覆之伊布洛芬之塗覆材料黏聚之方法、保存經塗覆之伊布洛芬之塗層之方法及使醫藥懸浮液中伊布洛芬通氣最小化之方法的實例性實施例。亦闡述藉由所揭示方法中之任一或多者製備之包含伊布洛芬的醫藥組合物。下文詳細闡述該等方法及醫藥組合物中之每一者。包含伊布洛芬之醫藥組合物可使用下述製備方法之特徵的任何組合來製備。This article describes the method of minimizing and/or preventing the adhesion of the coating material of the coated ibuprofen, the method of preserving the coating of the coated ibuprofen, and the ventilation of the ibuprofen in the pharmaceutical suspension An exemplary embodiment of the method of minimization. Also described are pharmaceutical compositions containing ibuprofen prepared by any one or more of the disclosed methods. Each of these methods and pharmaceutical compositions is described in detail below. The pharmaceutical composition containing ibuprofen can be prepared using any combination of the features of the following preparation methods.

圖1A、1B及1C圖解說明根據一些實施例之經塗覆之API顆粒(例如伊布洛芬)。在一些實施例中，API顆粒可與一或多種塗覆材料組合以產生經塗覆之API。此塗料可包含包括水溶性及/或水溶脹材料及水不溶性材料的材料(下文詳細闡述)。Figures 1A, 1B, and 1C illustrate coated API particles (e.g., ibuprofen) according to some embodiments. In some embodiments, API particles can be combined with one or more coating materials to produce a coated API. The coating may include materials including water-soluble and/or water-swellable materials and water-insoluble materials (explained in detail below).

舉例而言，圖1A顯示由塗覆材料顆粒104包圍之API顆粒102。為了達成圖1A之經塗覆之API顆粒，可將組合之API (即，API顆粒102)及一或多種塗覆材料(即，塗覆材料顆粒104)暴露於機械及/或熱能以產生API顆粒102之有序混合物，其包含將API顆粒102之表面分層之塗覆材料顆粒104之離散層。顯示圖1A之API顆粒102具有塗覆材料之離散顆粒之單一層。然而，API顆粒102可具有塗覆顆粒之兩個或更多個離散層。另外，圖2顯示未經塗覆之API顆粒之SEM影像。For example, FIG. 1A shows API particles 102 surrounded by coating material particles 104. In order to achieve the coated API particles of FIG. 1A, the combined API (ie, API particles 102) and one or more coating materials (ie, coating material particles 104) can be exposed to mechanical and/or thermal energy to generate API An ordered mixture of particles 102 comprising discrete layers of coating material particles 104 that layer the surface of API particles 102. It is shown that the API particles 102 of FIG. 1A have a single layer of discrete particles of coating material. However, the API particles 102 may have two or more discrete layers of coated particles. In addition, Figure 2 shows an SEM image of uncoated API particles.

圖1B展現由連續變形之膜層104包圍之API顆粒102。具體而言，圖1B顯示，所有塗覆材料顆粒104皆可為可變形的且當經受機械應力及/或升高之溫度時可變形。因此，由於所有塗覆材料皆包含可變形特徵，故圖1B之塗覆材料104在暴露於機械及/或熱能之後係相對平滑且連續之塗覆層。在一些實施例中，API顆粒102可具有兩個或更多個相對平滑且連續之塗覆層。如本文所用，「連續膜」可為包圍API顆粒之層，其係藉由熔融/軟化或以其他方式分解個別塗覆材料顆粒之一或多種可變形組分使得其包含包圍API顆粒之單一連續層而形成。圖3亦提供根據一些實施例之經塗覆之API顆粒之SEM影像。FIG. 1B shows API particles 102 surrounded by a continuously deformed film layer 104. Specifically, FIG. 1B shows that all the coating material particles 104 can be deformable and deformable when subjected to mechanical stress and/or elevated temperature. Therefore, since all coating materials include deformable features, the coating material 104 of FIG. 1B is a relatively smooth and continuous coating layer after being exposed to mechanical and/or thermal energy. In some embodiments, the API particles 102 may have two or more relatively smooth and continuous coating layers. As used herein, a "continuous film" may be a layer surrounding API particles, which is formed by melting/softening or otherwise decomposing one or more deformable components of individual coating material particles so that it contains a single continuous layer surrounding API particles Layers are formed. Figure 3 also provides SEM images of coated API particles according to some embodiments.

在一些實施例中，一或多種填充材料可為不可變形的，但可包埋於可變形塗覆層中。因此，連續膜可包含包埋於變形塗覆材料中之不可變形材料之固體顆粒。圖1C顯示連續膜104可包含部分包埋及/或包埋於連續膜104之變形塗覆材料內之一或多種不可變形材料之固體不可變形顆粒108。圖1B或1C之此連續膜104可確保塗層(例如，掩蔽API之味道之塗層)及延遲之API釋放。在一些實施例中，API顆粒102可具有兩個或更多個經不可變形之塗覆材料顆粒部分包埋及/或包埋之連續塗覆層。圖3亦提供顯示根據一些實施例之功能性塗覆之API顆粒的SEM影像。In some embodiments, one or more filler materials may be non-deformable, but may be embedded in the deformable coating layer. Therefore, the continuous film may contain solid particles of non-deformable material embedded in the deformable coating material. 1C shows that the continuous film 104 may include solid non-deformable particles 108 of one or more non-deformable materials partially embedded and/or embedded in the deformable coating material of the continuous film 104. The continuous film 104 of FIG. 1B or 1C can ensure coating (for example, a coating that masks the taste of API) and delayed API release. In some embodiments, the API particles 102 may have two or more continuous coating layers partially embedded and/or embedded by the non-deformable coating material particles. Figure 3 also provides SEM images showing functionally coated API particles according to some embodiments.

如本文所用術語「可變形」、「可變形組分」、「塗覆材料之可變形組分」及其他相關術語係指在經受機械應力及/或升高溫度時可分解之水溶性、水溶脹性及/或水不溶性材料的一或多種組分。As used herein, the terms “deformable”, “deformable component”, “deformable component of coating material” and other related terms refer to water-soluble, water-soluble components that can be decomposed when subjected to mechanical stress and/or elevated temperature. One or more components of swellable and/or water-insoluble materials.

在一些實施例中，經塗覆之API顆粒可包含伊布洛芬。在一些實施例中，經塗覆之API顆粒或醫藥組合物可包含30.0至90.0 % w/w伊布洛芬。在一些實施例中，經塗覆之API顆粒或醫藥組合物可包含40.0至85.0 % w/w、50.0至80.0 % w/w或70.0至80.0 % w/w伊布洛芬。在一些實施例中，經塗覆之API顆粒或醫藥組合物可包含超過40.0 % w/w、超過50.0 % w/w、超過60.0 % w/w、超過65 % w/w、超過70.0 % w/w、超過75.0 % w/w、超過80.0 % w/w或超過85.0 % w/w伊布洛芬。在一些實施例中，經塗覆之API顆粒或醫藥組合物可包含少於90.0 % w/w、少於85.0 % w/w、少於80.0 % w/w、少於75.0 % w/w、少於70.0 % w/w、少於60.0 % w/w、少於50.0 % w/w或少於40.0 % w/w伊布洛芬。In some embodiments, the coated API particles may include ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may contain 30.0 to 90.0% w/w ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may include 40.0 to 85.0% w/w, 50.0 to 80.0% w/w, or 70.0 to 80.0% w/w ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may contain more than 40.0% w/w, more than 50.0% w/w, more than 60.0% w/w, more than 65% w/w, more than 70.0% w/w /w, more than 75.0% w/w, more than 80.0% w/w, or more than 85.0% w/w ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may contain less than 90.0% w/w, less than 85.0% w/w, less than 80.0% w/w, less than 75.0% w/w, Less than 70.0% w/w, less than 60.0% w/w, less than 50.0% w/w or less than 40.0% w/w ibuprofen.

包圍API顆粒102之塗層104可包含包括水溶性及/或水溶脹性材料及水不溶性材料之材料。在一些實施例中，此塗層可直接塗覆API顆粒(例如伊布洛芬)，或其可塗覆已經包含一或多個塗層之API顆粒。在一些實施例中，塗覆材料對API之比率可經最佳化以使過量塗覆材料最小化。舉例而言，塗覆材料可包含5-85% w/w、10-50%、15-30% API及塗覆材料混合物或醫藥組合物。在一些實施例中，塗覆材料可包含少於85%、少於80%、少於75%、少於70%、少於65%、少於60%、少於55%、少於50%、少於45%、少於40%、少於35%、少於30%、少於25%、少於20%、少於15%或少於10% API及塗覆材料混合物或醫藥組合物。在一些實施例中，塗覆材料可包括超過5%、超過10%、超過15%、超過20%、超過25%、超過30%、超過35%、超過40%、超過45%、超過50%、超過55%、超過60%、超過65%、超過70%或超過75% API及塗覆材料混合物或醫藥組合物。在一些實施例中，塗覆材料百分比可包括兩個或更多個塗覆材料層。The coating 104 surrounding the API particles 102 may include materials including water-soluble and/or water-swellable materials and water-insoluble materials. In some embodiments, this coating can directly coat API particles (for example, Ibuprofen), or it can coat API particles that already contain one or more coatings. In some embodiments, the ratio of coating material to API can be optimized to minimize excess coating material. For example, the coating material may include 5-85% w/w, 10-50%, 15-30% API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material may include less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50% , Less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15% or less than 10% API and coating material mixture or pharmaceutical composition . In some embodiments, the coating material may include more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50% , More than 55%, more than 60%, more than 65%, more than 70% or more than 75% API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material percentage may include two or more coating material layers.

塗覆材料之水溶脹性材料可為包含約0.5µm至約20µm或約1µm至約10µm之中值粒度的顆粒。在一些實施例中，水溶脹性材料可比伊布洛芬小約十倍，以實現有序混合及塗覆。吸收水後，水溶脹性材料可溶脹，使得水溶脹性顆粒之直徑增加至少約120-600%。塗覆材料或醫藥組合物可包含0至8 % w/w或0.1至0.9 % w/w水溶脹性材料。在一些實施例中，塗覆材料或醫藥組合物可包含0.5至6.0 % w/w、1.0至4.0 % w/w、1.5至3.5 % w/w或2.0至3.0 % w/w水溶脹性材料。在一些實施例中，塗覆材料或醫藥組合物可包含少於8.0 % w/w、少於6.0 % w/w、少於4.0 % w/w、少於2.0 % w/w、少於1.0 % w/w或少於0.5 % w/w水溶脹性材料。在一些實施例中，塗覆材料或醫藥組合物可包含大於0.1 % w/w、大於0.5 % w/w、大於1.0 % w/w、大於2.0 % w/w、大於3.0 w/w %、大於5.0 % w/w或大於6.0 % w/w水溶脹性材料。塗覆材料之水溶脹性材料可在機械應力及/或升高溫度下變形(下文詳細闡述)。水溶脹性材料可為交聚維酮、交聯羧甲纖維素、澱粉羥乙酸鈉或醫藥工業中用作用於製錠之添加劑或摻合物之任何其他適宜崩解劑中的任一或多者。The water-swellable material of the coating material may be particles containing a median particle size of about 0.5 µm to about 20 µm or about 1 µm to about 10 µm. In some embodiments, the water-swellable material can be about ten times smaller than ibuprofen to achieve orderly mixing and coating. After absorbing water, the water-swellable material can swell so that the diameter of the water-swellable particles increases by at least about 120-600%. The coating material or the pharmaceutical composition may contain 0 to 8% w/w or 0.1 to 0.9% w/w water swellable material. In some embodiments, the coating material or pharmaceutical composition may comprise 0.5 to 6.0% w/w, 1.0 to 4.0% w/w, 1.5 to 3.5% w/w, or 2.0 to 3.0% w/w water swellable material . In some embodiments, the coating material or pharmaceutical composition may comprise less than 8.0% w/w, less than 6.0% w/w, less than 4.0% w/w, less than 2.0% w/w, less than 1.0 % w/w or less than 0.5% w/w water swellable material. In some embodiments, the coating material or the pharmaceutical composition may comprise greater than 0.1% w/w, greater than 0.5% w/w, greater than 1.0% w/w, greater than 2.0% w/w, greater than 3.0 w/w%, Water-swellable materials greater than 5.0% w/w or greater than 6.0% w/w. The water-swellable material of the coating material can deform under mechanical stress and/or elevated temperature (explained in detail below). The water-swellable material can be any one or more of crospovidone, croscarmellose, sodium starch glycolate, or any other suitable disintegrant used in the pharmaceutical industry as additives or blends for tablet preparation. By.

塗覆材料之水溶性材料亦可為包含約0.5µm至約20µm或約1µm至約10µm之中值粒度的顆粒。在一些實施例中，水溶性材料可比伊布洛芬小約十倍，以實現有序混合及塗覆。水溶性材料可在中性pH下及在20℃下在水中具有至少約50 mg/ml之水溶解度。此外，水溶性材料可具有約3-60 µg/m² s之固有溶解速率。塗覆材料之水溶性材料可在機械能及/或熱能下變形。塗覆材料或醫藥組合物可包含0至35 % w/w水溶性材料。在一些實施例中，塗覆材料或醫藥組合物可包含0.5至25 % w/w、1.0至15 % w/w、1.5至10 % w/w或2.0至3.0 % w/w水溶性材料。在一些實施例中，塗覆材料或醫藥組合物可包含少於35 % w/w、少於30 % w/w、少於25 % w/w、少於20 % w/w、少於15 % w/w、少於10% w/w、少於5.0 % w/w、少於4.5 % w/w、少於4.0 % w/w、少於3.5 % w/w、少於3.0 % w/w、少於2.5 % w/w、少於2.0 % w/w、少於1.5 % w/w、少於1.0 % w/w或少於0.5 % w/w水溶性材料。在一些實施例中，塗覆材料或醫藥組合物可包含超過0.1 % w/w、超過0.5 % w/w、超過1.0 % w/w、超過1.5 % w/w、超過2.0 % w/w、超過2.5 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過5.0 % w/w、超過8.0 % w/w、超過10 % w/w、超過15 % w/w、超過20 % w/w、超過25 % w/w或超過30 % w/w水溶性材料。水溶性材料可為蔗糖、甘露醇、山梨醇、聚乙烯基吡咯啶酮、羥基丙基纖維素、乳糖、聚-(環氧乙烷)及任何其他適宜可微米化材料或多元醇中之一或多者。The water-soluble material of the coating material can also be particles containing a median particle size of about 0.5 µm to about 20 µm or about 1 µm to about 10 µm. In some embodiments, the water-soluble material may be about ten times smaller than ibuprofen to achieve orderly mixing and coating. The water-soluble material may have a water solubility of at least about 50 mg/ml in water at a neutral pH and at 20°C. In addition, water-soluble materials may have an inherent dissolution rate of about 3-60 µg/m ² s. The water-soluble material of the coating material can deform under mechanical energy and/or thermal energy. The coating material or pharmaceutical composition may contain 0 to 35% w/w water-soluble material. In some embodiments, the coating material or pharmaceutical composition may include 0.5 to 25% w/w, 1.0 to 15% w/w, 1.5 to 10% w/w, or 2.0 to 3.0% w/w water-soluble material. In some embodiments, the coating material or pharmaceutical composition may contain less than 35% w/w, less than 30% w/w, less than 25% w/w, less than 20% w/w, less than 15% % w/w, less than 10% w/w, less than 5.0% w/w, less than 4.5% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w /w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, less than 1.0% w/w or less than 0.5% w/w water-soluble materials. In some embodiments, the coating material or pharmaceutical composition may contain more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, Over 2.5% w/w, over 3.0% w/w, over 4.0% w/w, over 5.0% w/w, over 8.0% w/w, over 10% w/w, over 15% w/w, over 20% w/w, more than 25% w/w or more than 30% w/w water-soluble materials. The water-soluble material can be one of sucrose, mannitol, sorbitol, polyvinylpyrrolidone, hydroxypropyl cellulose, lactose, poly-(ethylene oxide), and any other suitable micronizable material or polyol Or more.

除了上文論述之3-60 µg/m² s之固有溶解速率，所提供之方法亦可允許使用具有約60-300 µg/m² s之較高固有溶解速率之水溶性及/或水溶脹性材料。然而，具有較高固有溶解速率之塗覆材料之伊布洛芬應用疏水性二氧化矽進行乾塗覆。其中塗層包含具有較高固有溶解速率之水溶性及/或水溶脹性材料之乾塗覆伊布洛芬可增加伊布洛芬之崩解時間，使得其不能有效掩蔽伊布洛芬之味道。因此，用二氧化矽作為第二塗覆材料對伊布洛芬進行乾塗覆以減慢溶解速率可改良塗層之活體內掩味性能。經塗覆之伊布洛芬可包含0.5至35 % w/w二氧化矽。在一些實施例中，經塗覆之伊布洛芬或醫藥組合物可包含0.5至20 % w/w、0.5至10 % w/w或0.5至5 % w/w疏水性發煙二氧化矽。在一些實施例中，經塗覆之伊布洛芬或醫藥組合物可包含超過0.5 % w/w、超過1.0 % w/w、超過1.5 % w/w、超過2.0 % w/w、超過2.5 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過5.0 % w/w、超過10 % w/w、超過15 % w/w、超過20 % w/w、超過25 % w/w或超過30 % w/w疏水性發煙二氧化矽。在一些實施例中，經塗覆之伊布洛芬或醫藥組合物可包含少於35 % w/w、少於25 % w/w、少於15 % w/w、少於10 % w/w、少於5.0 % w/w、少於4.0 % w/w、少於3.5 % w/w、少於3.0 % w/w、少於2.5 % w/w、少於2.0 % w/w、少於1.5 % w/w或少於1.0 % w/w疏水性發煙二氧化矽。可使用之二氧化矽之實例包括(但不限於) Aerosil R972二氧化矽(Degussa)、CAB-O-SIL EH-5二氧化矽(Cabot)、OX-50二氧化矽(Degussa)、COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan))、P-500親水性二氧化矽(Catalyst & Chemical Ind. Co. Ltd (Japan))及TS5二氧化矽(Cabot)。此外，可用於用二氧化矽進行乾塗覆之適宜裝置包括(但不限於) Comil (U3 Quadro Comil of Quadro Pennsylvania, U.S.)、LabRAM (Resodyne Minnesota, U.S.)、Magnetically Assisted Impact Coater (MAIC, Aveka Minnesota, U.S.)及Fluid Energy Mill (FEM, Qualification Micronizer of Sturtevant Massachusetts U.S.)。In addition to the inherent dissolution rate of 3-60 µg/m ² s discussed above, the provided method can also allow the use of water soluble and/or water swelling with a higher inherent dissolution rate of about 60-300 µg/m ² s Sexual material. However, ibprofen, which is a coating material with a higher inherent dissolution rate, should be dry coated with hydrophobic silica. The coating contains water-soluble and/or water-swellable materials with a higher inherent dissolution rate. Dry coating of Ibuprofen can increase the disintegration time of Ibuprofen, making it unable to effectively mask the taste of Ibuprofen. . Therefore, dry coating of ibuprofen with silica as the second coating material to slow down the dissolution rate can improve the in-vivo taste masking performance of the coating. The coated ibuprofen may contain 0.5 to 35% w/w silica. In some embodiments, the coated ibuprofen or pharmaceutical composition may comprise 0.5 to 20% w/w, 0.5 to 10% w/w, or 0.5 to 5% w/w hydrophobic fuming silica . In some embodiments, the coated ibuprofen or pharmaceutical composition may contain more than 0.5% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5 % w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w or more than 30% w/w hydrophobic fuming silica. In some embodiments, the coated ibuprofen or pharmaceutical composition may comprise less than 35% w/w, less than 25% w/w, less than 15% w/w, less than 10% w/w w, less than 5.0% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, Less than 1.5% w/w or less than 1.0% w/w hydrophobic fuming silica. Examples of silicon dioxide that can be used include (but are not limited to) Aerosil R972 silicon dioxide (Degussa), CAB-O-SIL EH-5 silicon dioxide (Cabot), OX-50 silicon dioxide (Degussa), COSM055 ( Catalyst & Chemical Ind. Co. Ltd (Japan)), P-500 hydrophilic silica (Catalyst & Chemical Ind. Co. Ltd (Japan)) and TS5 silica (Cabot). In addition, suitable devices that can be used for dry coating with silicon dioxide include (but are not limited to) Comil (U3 Quadro Comil of Quadro Pennsylvania, US), LabRAM (Resodyne Minnesota, US), Magnetically Assisted Impact Coater (MAIC, Aveka Minnesota) , US) and Fluid Energy Mill (FEM, Qualification Micronizer of Sturtevant Massachusetts US).

醫藥組合物可藉由將醫藥懸浮液計量至預成型泡罩包中來製備。在一些實施例中，冷凍乾燥之經口崩解之錠劑可藉由將懸浮液計量至泡罩包中來製備。在一些實施例中，計量幫浦按體積泵送，但該過程按重量控制。因此，為了確保自一個劑型至下一劑型之含量均勻性，可控制計量過程，使得經計量懸浮液之體積對重量百分比係一致的。舉例而言，體積對重量%可在10%內、在8%內、在6%內、在5%內、在4%內、在3%內、在2%內、在1.5%內、在1%內、在0.5%內或在0.25%內一致。在一些實施例中，經計量醫藥懸浮液之重量係在目標重量之10%內、8%內、6%內、5%內、4%內、2.5%內、2%內、1.5%內、1%內、0.5%內或0.25%內。另外，醫藥懸浮液之黏度應保持足夠低以易於計量。如上所述，醫藥懸浮液之高黏度可導致計量期間之泵滯塞。The pharmaceutical composition can be prepared by metering the pharmaceutical suspension into a preformed blister pack. In some embodiments, freeze-dried orally disintegrating lozenges can be prepared by metering the suspension into a blister pack. In some embodiments, the metering pump is pumped by volume, but the process is controlled by weight. Therefore, in order to ensure the uniformity of content from one dosage form to the next, the metering process can be controlled so that the volume of the metered suspension is consistent with the weight percentage. For example, the volume to weight% can be within 10%, within 8%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1.5%, within Consistent within 1%, within 0.5%, or within 0.25%. In some embodiments, the weight of the metered pharmaceutical suspension is within 10%, within 8%, within 6%, within 5%, within 4%, within 2.5%, within 2%, within 1.5%, Within 1%, 0.5% or 0.25%. In addition, the viscosity of the pharmaceutical suspension should be kept low enough for easy measurement. As mentioned above, the high viscosity of pharmaceutical suspensions can cause pump blockage during metering.

塗覆材料之水不溶性材料亦可為包含平均粒度小於伊布洛芬之平均粒度的顆粒。舉例而言，水不溶性材料可包含約1-20 µm、約1-12 µm、約2-10 µm、約5-12 µm或約5-6 µm之平均粒度。在一些實施例中，水不溶性材料可比伊布洛芬小約十倍，以實現有序混合及塗覆。塗覆材料之水不溶性材料可在機械應力及/或升高溫度下變形。塗覆材料或醫藥組合物可包含5至70 % w/w、10至60 % w/w、10至50 % w/w、10至40 % w/w、10至35 % w/w或15至30 % w/w水不溶性材料。在一些實施例中，塗覆材料或醫藥組合物可包含超過5 % w/w、超過10 % w/w、超過15 % w/w、超過20 % w/w、超過25 % w/w、超過30 % w/w、超過35 % w/w或超過40 % w/w水不溶性材料。在一些實施例中，塗覆材料或醫藥組合物可包含少於70 % w/w、少於60 % w/w、少於50 % w/w、少於45 % w/w、少於40 % w/w、少於35 % w/w或少於30 % w/w水不溶性材料。適宜水不溶性材料之實例包括(但不限於)乙基纖維素、聚乙烯、聚丙烯、聚四氟乙烯、巴西棕櫚蠟、小燭樹蠟、蓖麻蠟、聚醯胺蠟及/或合成蠟。The water-insoluble material of the coating material may also contain particles having an average particle size smaller than that of Ibuprofen. For example, the water-insoluble material may include an average particle size of about 1-20 µm, about 1-12 µm, about 2-10 µm, about 5-12 µm, or about 5-6 µm. In some embodiments, the water-insoluble material may be about ten times smaller than ibuprofen to achieve orderly mixing and coating. The water-insoluble material of the coating material can deform under mechanical stress and/or elevated temperature. The coating material or pharmaceutical composition may comprise 5 to 70% w/w, 10 to 60% w/w, 10 to 50% w/w, 10 to 40% w/w, 10 to 35% w/w or 15 Up to 30% w/w water insoluble material. In some embodiments, the coating material or pharmaceutical composition may comprise more than 5% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w, Water-insoluble materials exceeding 30% w/w, exceeding 35% w/w or exceeding 40% w/w. In some embodiments, the coating material or pharmaceutical composition may contain less than 70% w/w, less than 60% w/w, less than 50% w/w, less than 45% w/w, less than 40% w/w, % w/w, less than 35% w/w or less than 30% w/w water-insoluble materials. Examples of suitable water-insoluble materials include (but are not limited to) ethyl cellulose, polyethylene, polypropylene, polytetrafluoroethylene, carnauba wax, candelilla wax, castor wax, polyamide wax and/or synthetic wax .

在一些實施例中，機械能及/或熱能可用於使一或多種水可溶性材料、水溶脹性材料及/或水不溶性材料變形。舉例而言，可使用PharmaRAM II聲學混合器、RAM5 Pharma混合器或RAM55 Pharma混合器(Resodyn混合器)對功能性塗覆之伊布洛芬施加機械應力。在此聲學混合過程期間，經塗覆之伊布洛芬可暴露於高達100倍之重力(100G加速度)下。該等高力引起顆粒-顆粒碰撞，其產生呈熱形式之能量，其可用於使API上之一或多種水可溶性材料、水溶脹性材料及/或水不溶性材料變形。In some embodiments, mechanical energy and/or thermal energy can be used to deform one or more water-soluble materials, water-swellable materials, and/or water-insoluble materials. For example, a PharmaRAM II acoustic mixer, RAM5 Pharma mixer or RAM55 Pharma mixer (Resodyn mixer) can be used to apply mechanical stress to the functionally coated ibuprofen. During this acoustic mixing process, the coated ibuprofen can be exposed to up to 100 times the gravity (100G acceleration). These high forces cause particle-particle collisions, which generate energy in the form of heat, which can be used to deform one or more water-soluble materials, water-swellable materials, and/or water-insoluble materials on the API.

然而，上述塗覆過程亦可產生「鬆散的」或「游離的」塗覆材料顆粒。圖2係未經塗覆之API顆粒之SEM影像。圖3係經塗覆之API顆粒312之SEM影像。「鬆散的」或「游離的」塗覆材料顆粒314不與經塗覆之API顆粒312結合。However, the aforementioned coating process can also produce "loose" or "free" coating material particles. Figure 2 is an SEM image of uncoated API particles. Figure 3 is an SEM image of the coated API particles 312. The "loose" or "free" coating material particles 314 do not bind to the coated API particles 312.

一旦篩分，可將經塗覆之伊布洛芬混入基質溶液/懸浮液中以形成醫藥懸浮液(例如經塗覆之伊布洛芬加基質溶液/懸浮液)並按重量計量至預成型泡罩包之袋中以形成醫藥懸浮液之等分試樣。一旦計量，具有醫藥懸浮液之等分試樣之泡罩包在零下條件下冷凍。將經計量之醫藥懸浮液之冷凍等分試樣保持冷凍，直至其準備好冷凍乾燥，在此期間去除醫藥懸浮液之溶劑以形成醫藥組合物。Once sieved, the coated ibuprofen can be mixed into the matrix solution/suspension to form a pharmaceutical suspension (eg coated ibuprofen plus matrix solution/suspension) and measured by weight to a preform To form an aliquot of the pharmaceutical suspension in the bag of the blister pack. Once metered, the blister pack with an aliquot of the pharmaceutical suspension is frozen under sub-zero conditions. The frozen aliquot of the metered pharmaceutical suspension is kept frozen until it is ready for freeze drying, during which time the solvent of the pharmaceutical suspension is removed to form the pharmaceutical composition.

基質溶液/懸浮液可包括基質形成劑、結構形成劑及溶劑。舉例而言，基質形成劑可包括任何水溶性或水分散性材料，其對於功能性塗覆之伊布洛芬係藥理學上可接受的或惰性的。在一些實施例中，基質形成劑可為多肽，例如明膠。明膠可至少部分經水解(藉由在水中加熱)。其他適宜基質形成劑材料包括(但不限於)多醣，例如水解之聚葡萄糖、糊精、及海藻酸鹽、聚乙烯醇、聚乙烯基吡咯啶酮及/或***樹膠。在一些實施例中，醫藥組合物(例如經口崩解之錠劑)中之基質的量可為1-30 % w/w。在一些實施例中，基質之量可少於30 % w/w、少於25 % w/w、少於20 % w/w、少於15 % w/w、少於10 % w/w、少於5 % w/w或少於3 % w/w。在一些實施例中，基質之量可超過1 % w/w、超過3 % w/w、超過5 % w/w、超過10 % w/w、超過15 % w/w、超過20 % w/w或超過25 % w/w。The matrix solution/suspension may include matrix forming agents, structure forming agents, and solvents. For example, the matrix forming agent may include any water-soluble or water-dispersible material that is pharmacologically acceptable or inert to the functionally coated ibuprofen. In some embodiments, the matrix forming agent may be a polypeptide, such as gelatin. Gelatin can be at least partially hydrolyzed (by heating in water). Other suitable matrix forming agent materials include, but are not limited to, polysaccharides, such as hydrolyzed polydextrose, dextrin, and alginate, polyvinyl alcohol, polyvinylpyrrolidone and/or gum arabic. In some embodiments, the amount of the base in the pharmaceutical composition (for example, an orally disintegrating lozenge) may be 1-30% w/w. In some embodiments, the amount of matrix may be less than 30% w/w, less than 25% w/w, less than 20% w/w, less than 15% w/w, less than 10% w/w, Less than 5% w/w or less than 3% w/w. In some embodiments, the amount of matrix may exceed 1% w/w, exceed 3% w/w, exceed 5% w/w, exceed 10% w/w, exceed 15% w/w, exceed 20% w/ w or more than 25% w/w.

在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之基質形成劑的量可為約0.1至10 % w/w。在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之基質形成劑的量可包括1.0至8.0 % w/w或2.0至5.0 % w/w。在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之基質形成劑的量可包括超過0.1 % w/w、超過0.5 % w/w、超過1.0 % w/w、超過2.0 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過4.5 % w/w、超過5.0 % w/w或超過8.0 % w/w。在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之基質形成劑的量可包括少於10 % w/w、少於8.0 % w/w、少於6.0 % w/w、少於5.0 % w/w、少於4.0 % w/w、少於3.0 % w/w、少於2.5 % w/w、少於2.0 % w/w、少於1.5 % w/w或少於1.0 % w/w。在一些實施例中，醫藥組合物中之基質形成劑的量可為約3-15% w/w、約4-10% w/w或約4-7% w/w。在一些實施例中，醫藥組合物中之基質形成劑的量可包括超過0.1 % w/w、超過0.5 % w/w、超過1.0 % w/w、超過2.0 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過5.0 % w/w、超過6.0 % w/w、超過7.0 % w/w、超過8.0 % w/w、超過9.0 % w/w、超過10.0 % w/w、超過11.0 % w/w、超過12.0 % w/w、超過13.0 % w/w或超過14.0 % w/w。在一些實施例中，醫藥組合物中之基質形成劑的量可包括少於15 % w/w、少於14.0 % w/w、少於13.0 % w/w、少於12.0 % w/w、少於10.0 % w/w、少於9.0 % w/w、少於8 % w/w、少於7 % w/w、少於6 % w/w、少於5 % w/w或少於4.0 % w/w。In some embodiments, the amount of matrix forming agent in the matrix solution/suspension or pharmaceutical suspension may be about 0.1 to 10% w/w. In some embodiments, the amount of matrix forming agent in the matrix solution/suspension or pharmaceutical suspension may include 1.0 to 8.0% w/w or 2.0 to 5.0% w/w. In some embodiments, the amount of the matrix forming agent in the matrix solution/suspension or pharmaceutical suspension may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/ w, more than 3.0% w/w, more than 4.0% w/w, more than 4.5% w/w, more than 5.0% w/w, or more than 8.0% w/w. In some embodiments, the amount of matrix forming agent in the matrix solution/suspension or pharmaceutical suspension may include less than 10% w/w, less than 8.0% w/w, less than 6.0% w/w, less than 5.0% w/w, less than 4.0% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w. In some embodiments, the amount of matrix forming agent in the pharmaceutical composition may be about 3-15% w/w, about 4-10% w/w, or about 4-7% w/w. In some embodiments, the amount of matrix forming agent in the pharmaceutical composition may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w /w, more than 4.0% w/w, more than 5.0% w/w, more than 6.0% w/w, more than 7.0% w/w, more than 8.0% w/w, more than 9.0% w/w, more than 10.0% w/ w, more than 11.0% w/w, more than 12.0% w/w, more than 13.0% w/w, or more than 14.0% w/w. In some embodiments, the amount of matrix forming agent in the pharmaceutical composition may include less than 15% w/w, less than 14.0% w/w, less than 13.0% w/w, less than 12.0% w/w, Less than 10.0% w/w, less than 9.0% w/w, less than 8% w/w, less than 7% w/w, less than 6% w/w, less than 5% w/w or less 4.0% w/w.

基質之結構形成劑或增積劑可包括糖。舉例而言，適宜結構形成劑包括(但不限於)甘露醇、右旋糖、乳糖、半乳糖、甘胺酸、環糊精或其組合。結構形成劑可在冷凍乾燥中用作增積劑，此乃因其結晶以提供冷凍乾燥劑型之結構堅固性。在一些實施例中，基質溶液/懸浮液中之結構形成劑的量可為約0.1至10 % w/w。在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之結構形成劑的量可包括1.0至8.0 % w/w或1.5至5.0 % w/w。在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之結構形成劑的量可包括超過0.1 % w/w、超過0.5 % w/w、超過1.0 % w/w、超過2.0 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過5.0 % w/w或超過8.0 % w/w。在一些實施例中，基質溶液/懸浮液或醫藥懸浮液中之結構形成劑的量可包括少於10 % w/w、少於8.0 % w/w、少於6.0 % w/w、少於5.0 % w/w、少於4.0 % w/w、少於3.0 % w/w、少於2.5 % w/w、少於2.0 % w/w、少於1.5 % w/w或少於1.0 % w/w。在一些實施例中，醫藥組合物中之結構形成劑的量可為約3-15% w/w、約4-10% w/w或約4-7% w/w。在一些實施例中，醫藥組合物中之結構形成劑的量可包括超過0.1 % w/w、超過0.5 % w/w、超過1.0 % w/w、超過2.0 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過5.0 % w/w、超過6.0 % w/w、超過7.0 % w/w、超過8.0 % w/w、超過9.0 % w/w、超過10.0 % w/w、超過11.0 % w/w、超過12.0 % w/w、超過13.0 % w/w或超過14.0 % w/w。在一些實施例中，醫藥組合物中之結構形成劑的量可包括少於15 % w/w、少於14.0 % w/w、少於13.0 % w/w、少於12.0 % w/w、少於10.0 % w/w、少於9.0 % w/w、少於8 % w/w、少於7 % w/w、少於6 % w/w、少於5 % w/w或少於4.0 % w/w。The structure forming or accumulating agent of the matrix may include sugar. For example, suitable structure forming agents include, but are not limited to, mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, or combinations thereof. The structure forming agent can be used as a build-up agent in freeze-drying because it crystallizes to provide the structural firmness of the freeze-dried dosage form. In some embodiments, the amount of structure forming agent in the matrix solution/suspension may be about 0.1 to 10% w/w. In some embodiments, the amount of structure forming agent in the matrix solution/suspension or pharmaceutical suspension may include 1.0 to 8.0% w/w or 1.5 to 5.0% w/w. In some embodiments, the amount of structure forming agent in the matrix solution/suspension or pharmaceutical suspension may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/ w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, or more than 8.0% w/w. In some embodiments, the amount of structure forming agent in the matrix solution/suspension or pharmaceutical suspension may include less than 10% w/w, less than 8.0% w/w, less than 6.0% w/w, less than 5.0% w/w, less than 4.0% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w. In some embodiments, the amount of structure forming agent in the pharmaceutical composition may be about 3-15% w/w, about 4-10% w/w, or about 4-7% w/w. In some embodiments, the amount of the structure forming agent in the pharmaceutical composition may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w /w, more than 4.0% w/w, more than 5.0% w/w, more than 6.0% w/w, more than 7.0% w/w, more than 8.0% w/w, more than 9.0% w/w, more than 10.0% w/ w, more than 11.0% w/w, more than 12.0% w/w, more than 13.0% w/w, or more than 14.0% w/w. In some embodiments, the amount of the structure forming agent in the pharmaceutical composition may include less than 15% w/w, less than 14.0% w/w, less than 13.0% w/w, less than 12.0% w/w, Less than 10.0% w/w, less than 9.0% w/w, less than 8% w/w, less than 7% w/w, less than 6% w/w, less than 5% w/w or less 4.0% w/w.

在一些實施例中，基質溶液/懸浮液及醫藥懸浮液可包括黏度調節劑。舉例而言，根據本文提供之實施例之黏度調節劑可包括植物膠，例如黃原膠、藻膠、瓜爾膠或刺槐豆膠；蛋白質，例如膠原或明膠；糖，例如瓊脂、羧甲纖維素、果膠或卡拉膠；澱粉，例如竹芋澱粉、玉米澱粉、片栗(Katakuri)澱粉、馬鈴薯澱粉、西米或木薯澱粉；及/或其他適宜黏度調節劑。在一些實施例中，基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中之黏度調節劑的量可為0至0.2 % w/w或0.01至0.1 % w/w。在一些實施例中，基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中之黏度調節劑的量可大於0.01 % w/w、大於0.03 % w/w、大於0.05 % w/w、大於0.07 % w/w、大於0.1 % w/w、大於0.12 % w/w、大於0.15 % w/w或大於0.17 % w/w。在一些實施例中，基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中之黏度調節劑的量可少於0.2 % w/w、少於0.18 % w/w、少於0.15 % w/w、少於0.12 % w/w、少於0.1 % w/w、少於0.08 % w/w、少於0.06 % w/w或少於0.03 % w/w。In some embodiments, matrix solutions/suspensions and pharmaceutical suspensions may include viscosity modifiers. For example, the viscosity modifier according to the embodiments provided herein may include vegetable gums, such as xanthan gum, algin, guar gum, or locust bean gum; proteins, such as collagen or gelatin; sugars, such as agar, carboxymethyl cellulose Starch, pectin or carrageenan; starches, such as arrowroot starch, corn starch, Katakuri starch, potato starch, sago or tapioca starch; and/or other suitable viscosity regulators. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition may be 0 to 0.2% w/w or 0.01 to 0.1% w/w. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition may be greater than 0.01% w/w, greater than 0.03% w/w, greater than 0.05% w/w, greater than 0.07 % w/w, greater than 0.1% w/w, greater than 0.12% w/w, greater than 0.15% w/w or greater than 0.17% w/w. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition can be less than 0.2% w/w, less than 0.18% w/w, less than 0.15% w/w , Less than 0.12% w/w, less than 0.1% w/w, less than 0.08% w/w, less than 0.06% w/w or less than 0.03% w/w.

基質溶液/懸浮液及醫藥懸浮液之溶劑可為水，但懸浮液溶液亦可包括共溶劑。在一些實施例中，溶劑可二乙醇、醇、異丙醇、其他低級烷醇、水(例如，純化水)或其組合。舉例而言，適宜溶劑及/或共溶劑可為醇，例如第三丁基醇。在一些實施例中，醫藥懸浮液之剩餘餘量為溶劑(即Q.S. 100%)。The solvent of the matrix solution/suspension and the pharmaceutical suspension may be water, but the suspension solution may also include a co-solvent. In some embodiments, the solvent may be diethanol, alcohol, isopropanol, other lower alkanols, water (e.g., purified water), or a combination thereof. For example, the suitable solvent and/or co-solvent may be an alcohol, such as tertiary butyl alcohol. In some embodiments, the remaining balance of the pharmaceutical suspension is solvent (ie, Q.S. 100%).

基質溶液/懸浮液及醫藥懸浮液亦可含有額外醫藥上可接受之試劑或賦形劑。該等額外醫藥上可接受之試劑或賦形劑包括(但不限於)糖、無機鹽(例如氯化鈉及矽酸鋁)、改質澱粉、防腐劑、抗氧化劑、黏度增強劑、著色劑、矯味劑、pH調節劑、甜味劑、掩味劑及其組合。適宜著色劑可包括紅色、黑色及黃色氧化鐵及FD & C染料(例如2號FD & C藍及40號FD & C紅)及其組合。適宜矯味劑可包括薄荷味、樹莓味、甘草味、橙味、檸檬味、葡萄柚味、焦糖味、香草味、櫻桃味及葡萄味矯味劑以及該等之組合。適宜pH調節劑可包括檸檬酸、酒石酸、磷酸、鹽酸、馬來酸、氫氧化鈉(例如，3% w/w氫氧化鈉溶液)及其組合。適宜甜味劑可包括阿斯巴甜、乙醯舒泛K及索馬甜及其組合。適宜掩味劑可包括碳酸氫鈉、離子交換樹脂、環糊精包涵合物、吸附物或微囊封活性物及其組合。若需要，熟習此項技術者可容易地確定該等各種額外賦形劑之適宜量。最小化及/或防止經塗覆之伊布洛芬之塗覆材料的黏聚The matrix solution/suspension and pharmaceutical suspension may also contain additional pharmaceutically acceptable reagents or excipients. Such additional pharmaceutically acceptable reagents or excipients include (but are not limited to) sugars, inorganic salts (such as sodium chloride and aluminum silicate), modified starches, preservatives, antioxidants, viscosity enhancers, coloring agents , Flavoring agents, pH regulators, sweeteners, taste masking agents and combinations thereof. Suitable colorants may include red, black and yellow iron oxides and FD & C dyes (such as No. 2 FD & C Blue and No. 40 FD & C Red) and combinations thereof. Suitable flavoring agents can include mint flavor, raspberry flavor, licorice flavor, orange flavor, lemon flavor, grapefruit flavor, caramel flavor, vanilla flavor, cherry flavor and grape flavor flavors and combinations thereof. Suitable pH adjusting agents may include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide (for example, 3% w/w sodium hydroxide solution), and combinations thereof. Suitable sweeteners may include aspartame, acetosulfame K, thaumatin and combinations thereof. Suitable taste masking agents may include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents or microencapsulated actives and combinations thereof. If necessary, those skilled in the art can easily determine the appropriate amount of these various additional excipients. Minimize and/or prevent the cohesion of the coated ibuprofen coating material

下文闡述製備包含伊布洛芬之醫藥組合物之方法，其使過量塗覆材料之量及/或過量塗覆材料在儲存時之黏聚量最小化。The following describes a method of preparing a pharmaceutical composition containing ibuprofen, which minimizes the amount of excess coating material and/or the amount of cohesion of excess coating material during storage.

根據一些實施例之方法包括去除過量塗覆材料顆粒以最小化及/或防止醫藥產品中塗覆材料之黏聚。在一些實施例中，方法可包括篩分原始伊布洛芬及/或經塗覆之伊布洛芬。具體地，所提供之方法可包括篩分伊布洛芬及/或經塗覆之伊布洛芬以去除任何不期望顆粒，例如過量塗覆材料顆粒。根據所揭示之實施例之篩分製程可幫助防止及/或最小化可不利地影響最終產品之崩解時間及/或溶解速率之塗覆材料黏聚的潛能。方法亦可包括最佳化該過程之塗覆及/或計量比。The method according to some embodiments includes removing excess coating material particles to minimize and/or prevent the cohesion of the coating material in the medical product. In some embodiments, the method may include sieving the original ibuprofen and/or the coated ibuprofen. Specifically, the provided method may include sieving Ibuprofen and/or coated Ibuprofen to remove any undesired particles, such as excessive coating material particles. The sieving process according to the disclosed embodiments can help prevent and/or minimize the potential for cohesion of coating materials that can adversely affect the disintegration time and/or dissolution rate of the final product. The method may also include optimizing the coating and/or metering ratio of the process.

根據本文所述之實施例之用於最小化及/或防止塗覆材料顆粒之黏聚的方法可應用於用於塗覆伊布洛芬之乾燥、無溶劑混合過程。因此，下文在用於塗覆伊布洛芬之一或多種乾燥、無溶劑混合過程之上下文中闡述所提供之方法。然而，亦可使用塗覆/囊封過程之其他變化形式。舉例而言，可使用糖塗覆、膜塗覆、微囊封之其他變化形式、壓縮塗覆、乾塗覆之其他變化形式、熔融塗覆、浸塗、轉模塗覆、靜電塗覆及/或其他適宜類型之塗覆。The method for minimizing and/or preventing agglomeration of coating material particles according to the embodiments described herein can be applied to a dry, solvent-free mixing process for coating ibprofen. Therefore, the provided method is described below in the context of one or more dry, solvent-free mixing processes for applying ibuprofen. However, other variations of the coating/encapsulation process can also be used. For example, sugar coating, film coating, other variations of microencapsulation, compression coating, other variations of dry coating, melt coating, dip coating, rotary die coating, electrostatic coating, and / Or other suitable types of coating.

通常，用於塗覆伊布洛芬之無溶劑混合過程包括將塗覆材料與伊布洛芬混合以製備經塗覆之伊布洛芬。然後對經塗覆之伊布洛芬施加機械及/或熱應力，使可變形塗覆材料變形，產生包圍伊布洛芬之連續膜。然後將經塗覆之伊布洛芬與基質溶液/懸浮液混合以形成醫藥懸浮液。可將包含經塗覆之伊布洛芬之醫藥懸浮液計量至預成型之模具(例如泡罩包)中，且進一步處理以產生可分配之醫藥組合物(例如凍乾物、薄片、錠劑等)。Generally, the solvent-free mixing process for coating ibuprofen includes mixing the coating material with ibuprofen to prepare coated ibuprofen. Then, mechanical and/or thermal stress is applied to the coated ibuprofen to deform the deformable coating material to produce a continuous film surrounding the ibuprofen. The coated ibuprofen is then mixed with the matrix solution/suspension to form a pharmaceutical suspension. The pharmaceutical suspension containing the coated ibuprofen can be metered into a preformed mold (such as a blister pack) and further processed to produce a dispensable pharmaceutical composition (such as a lyophilisate, flake, lozenge, etc.) ).

然而，在儲存最終產品(即醫藥組合物)時，任何未與經塗覆之伊布洛芬結合之過量塗覆材料顆粒皆可黏聚。黏聚之量及/或嚴重程度可隨時間增加。過量塗覆材料之黏聚可增加崩解時間及/或降低醫藥產品之溶解速率，且不利地影響塗覆材料之任何功能性質。增加之崩解時間亦可導致不可接受之活體內分散及口感特徵。However, during storage of the final product (ie, pharmaceutical composition), any excess particles of the coating material that are not combined with the coated ibuprofen can cohere. The amount and/or severity of cohesion can increase over time. The cohesion of excessive coating material can increase the disintegration time and/or reduce the dissolution rate of the medical product, and adversely affect any functional properties of the coating material. The increased disintegration time can also lead to unacceptable in vivo dispersion and mouthfeel characteristics.

因此，已發現，藉由篩分經塗覆之伊布洛芬，可去除過量塗覆材料，從而使過量塗覆材料在儲存時之黏聚量最小化。此外，一些實施例包括最佳化塗覆比(塗覆材料之量對未經塗覆之伊布洛芬之量之比率)及最佳化計量比率(經塗覆之伊布洛芬之量對包含所有其他非活性成份之水溶液基質之量之比率)亦可使過量塗覆材料顆粒之黏聚最小化。Therefore, it has been found that by sieving the coated ibuprofen, the excess coating material can be removed, thereby minimizing the amount of cohesion of the excess coating material during storage. In addition, some embodiments include the optimized coating ratio (the ratio of the amount of coating material to the amount of uncoated ibprofen) and the optimized metering ratio (the amount of coated ibprofen The ratio to the amount of the aqueous matrix containing all other inactive ingredients) can also minimize the agglomeration of excess coating material particles.

本文提供之實施例可應用於使用乾燥、無溶劑方法產生之經塗覆之伊布洛芬。根據本文所述之實施例之一些混合方法包括用掩味塗層對伊布洛芬進行塗覆。該等塗層可控制口腔可分散醫藥組合物之崩解時間及/或溶解速率，使得在經口投與時，當伊布洛芬在口中時之最初幾分鐘內延遲或顯著降低伊布洛芬之釋放，但在吞嚥後經口投與後30分鐘內釋放令人滿意之量的伊布洛芬。(舉例而言，伊布洛芬之令人滿意之量可為無塗層下將釋放之伊布洛芬量的90%)。美國專利第9,107,851號(’851專利)係關於用於塗覆醫藥成份之實例性乾燥、無溶劑方法，其全文以引用方式併入本文中。The examples provided herein can be applied to coated ibuprofen produced using a dry, solvent-free method. Some mixing methods according to the embodiments described herein include coating ibuprofen with a taste-masking coating. These coatings can control the disintegration time and/or dissolution rate of the orally dispersible pharmaceutical composition, so that when administered orally, the ibprofen is delayed or significantly reduced in the first few minutes when ibprofen is in the mouth. Fen is released, but a satisfactory amount of ibuprofen is released within 30 minutes after oral administration after swallowing. (For example, a satisfactory amount of ibuprofen may be 90% of the amount of ibuprofen that will be released without coating). U.S. Patent No. 9,107,851 (the '851 patent) relates to an exemplary dry, solvent-free method for coating medicinal ingredients, which is incorporated herein by reference in its entirety.

然而，亦可使用塗覆/囊封過程之其他變化形式。舉例而言，可使用糖塗覆、膜塗覆、微囊封之其他變化形式、壓縮塗覆、乾塗覆之其他變化形式、熔融塗覆、浸塗、轉模塗覆、靜電塗覆及/或其他適宜類型之塗覆。However, other variations of the coating/encapsulation process can also be used. For example, sugar coating, film coating, other variations of microencapsulation, compression coating, other variations of dry coating, melt coating, dip coating, rotary die coating, electrostatic coating, and / Or other suitable types of coating.

另外，本文提供之具體數據與崩解時間有關。然而，崩解時間與溶解速率成反比。因此，數據亦固有地提供關於溶解速率之資訊。崩解時間可根據美國藥典所述之方法(崩解701)來量測。在一些實施例中，崩解時間可為2-30秒或5-20秒。在一些實施例中，崩解時間可少於30秒、少於25秒、少於20秒、少於15秒、少於10秒或少於5秒。在一些實施例中，崩解時間可大於2秒、大於5秒、大於10秒、大於15秒、大於20秒或大於25秒。類似地，溶解速率亦可根據美國藥典所述之方法(溶解711)來測試。In addition, the specific data provided in this article is related to the disintegration time. However, the disintegration time is inversely proportional to the dissolution rate. Therefore, the data also inherently provides information about the dissolution rate. The disintegration time can be measured according to the method described in the US Pharmacopoeia (Disintegration 701). In some embodiments, the disintegration time can be 2-30 seconds or 5-20 seconds. In some embodiments, the disintegration time may be less than 30 seconds, less than 25 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, or less than 5 seconds. In some embodiments, the disintegration time can be greater than 2 seconds, greater than 5 seconds, greater than 10 seconds, greater than 15 seconds, greater than 20 seconds, or greater than 25 seconds. Similarly, the dissolution rate can also be tested according to the method described in the US Pharmacopoeia (Dissolution 711).

在一些實施例中，可在塗覆過程之前對原始伊布洛芬進行篩分以獲得較窄之粒度範圍。舉例而言，可對原始伊布洛芬進行篩分以去除過大之顆粒及/或去除過小之顆粒。在一些實施例中，可使用多於一個篩網以去除某些顆粒。舉例而言，篩分裝置可包含一系列兩個或更多個篩網，以根據篩網之大小去除一定大小之顆粒。篩可併入真空轉移系統以將顆粒運送通過裝置之一系列篩網。另外，篩分裝置中可併入超音波探頭以改良材料流動並使處理期間篩網之堵塞最小化。In some embodiments, the original ibuprofen may be sieved before the coating process to obtain a narrower particle size range. For example, the original ibuprofen can be sieved to remove oversized particles and/or to remove undersized particles. In some embodiments, more than one screen may be used to remove certain particles. For example, the screening device may include a series of two or more screens to remove particles of a certain size according to the size of the screens. The screen can be incorporated into a vacuum transfer system to transport the particles through a series of screens in the device. In addition, ultrasonic probes can be incorporated into the screening device to improve material flow and minimize clogging of the screen during processing.

在一些實施例中，可使用30 µm至500 µm、50 µm至450 µm、100 µm至400 µm、150 µm至350 µm或200 µm至300 µm之篩孔大小對原始伊布洛芬進行篩分。在一些實施例中，可使用小於500 µm、小於450 µm、小於400 µm、小於350 µm、小於300 µm、小於250 µm、小於200 µm、小於150或小於100 µm之篩孔大小對原始伊布洛芬進行篩分。在一些實施例中，可使用大於30 µm、大於50 µm、大於100 µm、大於150 µm、大於200 µm、大於250 µm、大於300 µm、大於350 µm或大於400 µm之篩孔大小對原始伊布洛芬進行篩分。In some embodiments, sieve sizes of 30 µm to 500 µm, 50 µm to 450 µm, 100 µm to 400 µm, 150 µm to 350 µm, or 200 µm to 300 µm can be used to screen the original ibuprofen . In some embodiments, a mesh size of less than 500 µm, less than 450 µm, less than 400 µm, less than 350 µm, less than 300 µm, less than 250 µm, less than 200 µm, less than 150 or less than 100 µm can be used to compare the original Ibrahimovic Profen is sieved. In some embodiments, a mesh size greater than 30 µm, greater than 50 µm, greater than 100 µm, greater than 150 µm, greater than 200 µm, greater than 250 µm, greater than 300 µm, greater than 350 µm, or greater than 400 µm can be used to compare the original sieve size. Ibuprofen is screened.

一旦伊布洛芬已由塗覆材料塗覆而產生經塗覆之伊布洛芬，可對經塗覆之伊布洛芬進行篩分以去除過量塗覆材料及殘餘微細伊布洛芬，其可未經塗覆、部分經塗覆之或經塗覆。過量塗覆材料可包括任何不與經塗覆之伊布洛芬結合之塗覆材料顆粒。在儲存最終醫藥產品時，任何過量塗覆材料皆可黏聚。舉例而言，在過量塗覆顆粒及已經與伊布洛芬結合之塗覆顆粒之間可發生融合，從而防止原本將有助於單位或錠劑之崩解或經塗覆之伊布洛芬之溶解的介質進入。因此，過量塗覆材料之黏聚可引起投與時崩解時間增加及/或溶解速率降低。Once ibuprofen has been coated by the coating material to produce coated ibuprofen, the coated ibuprofen can be screened to remove excess coating material and residual fine ibuprofen, It can be uncoated, partially coated or coated. The excess coating material may include any coating material particles that do not bind to the coated ibuprofen. When storing the final medical product, any excess coating material can cohere. For example, fusion can occur between the excess coated particles and the coated particles that have been combined with ibprofen, thereby preventing the disintegration of the unit or lozenge or the coated ibprofen The dissolved medium enters. Therefore, the cohesion of excessive coating materials can cause an increase in disintegration time and/or a decrease in dissolution rate during administration.

然而，已確定，自經塗覆之伊布洛芬中篩分出過量塗覆材料之方法可使塗覆材料之黏聚最小化且維持最終產品之初始崩解時間及/或溶解速率。篩分製程可為間歇的或連續的。另外，除了上述對原始伊布洛芬實施之篩分製程之外或代替上述對原始伊布洛芬實施之篩分製程，可實施此篩分製程。在一些實施例中，未經塗覆、原始伊布洛芬及經塗覆之伊布洛芬之篩分製程參數可不同。However, it has been determined that the method of sieving out the excess coating material from the coated ibuprofen can minimize the cohesion of the coating material and maintain the initial disintegration time and/or dissolution rate of the final product. The screening process can be batch or continuous. In addition, this screening process can be implemented in addition to the above-mentioned screening process performed on the original ibuprofen or instead of the above-mentioned screening process performed on the original ibuprofen. In some embodiments, the screening process parameters of uncoated, virgin ibuprofen and coated ibuprofen may be different.

在一些實施例中，可對經塗覆之伊布洛芬進行篩分以去除平均粒度小於期望平均經塗覆之伊布洛芬粒度的塗覆材料顆粒。在一些實施例中，可使用多於一個篩網以去除某些顆粒。舉例而言，篩分裝置可包括一系列兩個或更多個篩網，以根據篩網之大小去除一定大小之顆粒。篩可併入真空轉移系統以將顆粒遞送至裝置之一系列篩網。另外，篩分裝置中可併入超音波探頭以改良材料流動並使處理期間篩網之堵塞最小化。可包括助流劑(例如二氧化矽)以促進移動穿過篩。舉例而言，用於塗覆伊布洛芬之塗覆材料可包含助流劑。相反，原始伊布洛芬可不具黏性且在篩分期間不需要助流劑之幫助。篩分製程可為間歇過程或連續過程。In some embodiments, the coated ibprofen may be sieved to remove particles of the coating material having an average particle size smaller than the expected average coated ibprofen particle size. In some embodiments, more than one screen may be used to remove certain particles. For example, the screening device may include a series of two or more screens to remove particles of a certain size according to the size of the screens. The screen can be incorporated into a vacuum transfer system to deliver the particles to a series of screens in the device. In addition, ultrasonic probes can be incorporated into the screening device to improve material flow and minimize clogging of the screen during processing. A glidant (such as silica) may be included to facilitate movement through the screen. For example, the coating material used to coat ibuprofen may include a glidant. In contrast, the original ibuprofen may not be viscous and does not require the aid of glidants during screening. The screening process can be a batch process or a continuous process.

可最佳化塗覆比(即塗覆材料之量對未經塗覆之伊布洛芬之量的比率)以最小化及/或防止過量塗覆材料之黏聚。舉例而言，在一些實施例中，塗覆比可在5-85%或10-50 % w/w塗覆材料對15-95%或50-90% w/w未經塗覆之伊布洛芬之範圍內。在一些實施例中，塗覆材料之量可少於80% w/w、少於70% w/w、少於60% w/w、少於50% w/w、少於40% w/w、少於30% w/w、少於20% w/w或少於10% w/w。在一些實施例中，塗覆材料之量可超過5% w/w、超過10% w/w、超過20% w/w、超過30% w/w、超過40% w/w、超過50% w/w、超過60% w/w或超過70% w/w。在一些實施例中，未經塗覆之伊布洛芬之量可少於95% w/w、少於85% w/w、少於75% w/w、少於65% w/w、少於55% w/w、少於45% w/w、少於35% w/w或少於25% w/w。在一些實施例中，未經塗覆之API之量可超過20% w/w、超過30% w/w、超過40% w/w、超過50% w/w、超過60% w/w、超過70% w/w、超過80% w/w或超過90% w/w。The coating ratio (that is, the ratio of the amount of coating material to the amount of uncoated ibprofen) can be optimized to minimize and/or prevent cohesion of excessive coating material. For example, in some embodiments, the coating ratio can be 5-85% or 10-50% w/w coating material to 15-95% or 50-90% w/w uncoated Ibrahimovic Within the range of Lofen. In some embodiments, the amount of coating material may be less than 80% w/w, less than 70% w/w, less than 60% w/w, less than 50% w/w, less than 40% w/ w, less than 30% w/w, less than 20% w/w or less than 10% w/w. In some embodiments, the amount of coating material may exceed 5% w/w, exceed 10% w/w, exceed 20% w/w, exceed 30% w/w, exceed 40% w/w, exceed 50% w/w, more than 60% w/w, or more than 70% w/w. In some embodiments, the amount of uncoated ibuprofen may be less than 95% w/w, less than 85% w/w, less than 75% w/w, less than 65% w/w, Less than 55% w/w, less than 45% w/w, less than 35% w/w or less than 25% w/w. In some embodiments, the amount of uncoated API may exceed 20% w/w, exceed 30% w/w, exceed 40% w/w, exceed 50% w/w, exceed 60% w/w, More than 70% w/w, more than 80% w/w or more than 90% w/w.

可最佳化計量比(即，經塗覆之伊布洛芬之量對包含所有非活性成份之基質溶液/懸浮液之量的比率)以最小化及/或防止過量塗覆材料之黏聚。舉例而言，在一些實施例中，計量比可在5-60% w/w經塗覆之伊布洛芬對40-95% w/w 基質溶液/懸浮液之範圍內。在一些實施例中，計量比可包括少於60% w/w、少於50% w/w、少於40% w/w、少於30% w/w、少於20% w/w或少於10% w/w經塗覆之伊布洛芬。在一些實施例中，計量比可包括超過5% w/w、超過10% w/w、超過20% w/w、超過30% w/w、超過40% w/w或超過50% w/w經塗覆之伊布洛芬。在一些實施例中，計量比可包括少於95% w/w、少於90% w/w、少於80% w/w、少於70% w/w、少於60% w/w或少於50% w/w基質溶液/懸浮液。在一些實施例中，計量比可包括超過40% w/w、超過50% w/w、超過60% w/w、超過70% w/w、超過80% w/w或超過90% w/w基質溶液/懸浮液。保存藉由乾燥、無溶劑混合方法產生且在懸浮液中混合之功能性塗覆之伊布洛芬The metering ratio (ie, the ratio of the amount of coated ibuprofen to the amount of matrix solution/suspension containing all inactive ingredients) can be optimized to minimize and/or prevent cohesion of excessive coating materials . For example, in some embodiments, the metering ratio may be in the range of 5-60% w/w coated ibuprofen to 40-95% w/w matrix solution/suspension. In some embodiments, the metering ratio may include less than 60% w/w, less than 50% w/w, less than 40% w/w, less than 30% w/w, less than 20% w/w, or Less than 10% w/w coated ibuprofen. In some embodiments, the metering ratio may include more than 5% w/w, more than 10% w/w, more than 20% w/w, more than 30% w/w, more than 40% w/w, or more than 50% w/ w Coated Ibuprofen. In some embodiments, the metering ratio may include less than 95% w/w, less than 90% w/w, less than 80% w/w, less than 70% w/w, less than 60% w/w, or Less than 50% w/w matrix solution/suspension. In some embodiments, the metering ratio may include more than 40% w/w, more than 50% w/w, more than 60% w/w, more than 70% w/w, more than 80% w/w, or more than 90% w/ w Matrix solution/suspension. Preserve functionally coated Ibuprofen produced by dry, solvent-free mixing method and mixed in suspension

本文提供之醫藥組合物及製備醫藥組合物之方法可包括在塗覆製程中添加疏水性發煙二氧化矽以提供包圍功能性塗覆之伊布洛芬之功能性塗層(或「第一塗層」)及/或部分或完全包埋於其中的保護層。添加此疏水性發煙二氧化矽層(或「第二層」)可為功能性塗覆之伊布洛芬之第一塗覆層提供保護層，且可使第一塗覆層受到將功能性塗覆之伊布洛芬混合至醫藥懸浮液中所需之剪切力之侵蝕最小化。The pharmaceutical composition provided herein and the method for preparing the pharmaceutical composition may include adding hydrophobic fuming silica in the coating process to provide a functional coating (or "first") surrounding the functionally coated ibuprofen. Coating") and/or a protective layer partially or completely embedded therein. The addition of this hydrophobic fuming silica layer (or "second layer") can provide a protective layer for the first coating layer of functionally coated ibuprofen, and can make the first coating layer be functional The erosion of the shear force required to mix the sexually coated ibuprofen into the pharmaceutical suspension is minimized.

通常，用於塗覆伊布洛芬之無溶劑混合方法包括將塗覆材料與伊布洛芬混合以產生功能性塗覆之伊布洛芬。然後對功能性塗覆之伊布洛芬施加機械及/或熱應力，以使可變形塗覆材料變形，從而產生包圍伊布洛芬之連續膜。然後將功能性塗覆之伊布洛芬與基質溶液或懸浮液混合以形成醫藥懸浮液。可將包含功能性塗覆之伊布洛芬之醫藥懸浮液計量至預成型模具(例如泡罩包)中，且進一步處理以製備可分配之醫藥組合物(例如凍乾物、薄片、錠劑等)。在一些實施例中，可分配之醫藥組合物可為口腔可分散之產品。理想地，最終可分配醫藥組合物中之伊布洛芬之最小量(若有的話)在經口投與之最初幾分鐘內溶解。伊布洛芬釋放之此延遲或顯著降低使得當口腔可分散產品在患者口中時伊布洛芬之味道被掩蔽。相反，一旦醫藥組合物通過胃腸道，伊布洛芬可釋放。Generally, the solvent-free mixing method for coating ibprofen includes mixing the coating material with ibprofen to produce functionally coated ibprofen. Then, mechanical and/or thermal stress is applied to the functionally coated ibuprofen to deform the deformable coating material, thereby producing a continuous film surrounding the ibuprofen. The functionally coated ibuprofen is then mixed with the matrix solution or suspension to form a pharmaceutical suspension. The pharmaceutical suspension containing functionally coated ibuprofen can be metered into a preformed mold (such as a blister pack), and further processed to prepare a dispensable pharmaceutical composition (such as a lyophilized product, flake, lozenge, etc.) ). In some embodiments, the dispensable pharmaceutical composition may be an orally dispersible product. Ideally, the smallest amount (if any) of ibuprofen in the final dispensable pharmaceutical composition will dissolve within the first few minutes of oral administration. This delay or significant reduction in the release of ibuprofen allows the taste of ibuprofen to be masked when the orally dispersible product is in the mouth of the patient. In contrast, once the pharmaceutical composition passes through the gastrointestinal tract, ibuprofen can be released.

然而，當將功能性塗覆之伊布洛芬混合至基質溶液/懸浮液中時，將顆粒混合至基質溶液/懸浮液中所需之剪切力可侵蝕伊布洛芬之功能性塗層。塗層之侵蝕可破壞或損害功能性塗層之性質。舉例而言，功能性塗層之侵蝕可破壞或損害功能性塗層之任何掩味性質，且允許伊布洛芬在口腔中經歷溶解。However, when the functionally coated Ibuprofen is mixed into the matrix solution/suspension, the shear force required to mix the particles into the matrix solution/suspension can attack the functional coating of Ibuprofen . The erosion of the coating can destroy or impair the properties of the functional coating. For example, erosion of the functional coating can destroy or impair any taste masking properties of the functional coating and allow ibuprofen to undergo dissolution in the oral cavity.

因此，已發現疏水性發煙二氧化矽以及用作功能性塗覆之伊布洛芬之助流劑以幫助下游處理，亦可用於提供包圍功能性塗覆之伊布洛芬及/或部分或完全包埋於其中的疏水性屏障層。具體地，由疏水性發煙二氧化矽形成之疏水性屏障層可在醫藥懸浮液之製備及功能性塗覆之伊布洛芬之其他下游處理期間保護功能性塗覆之伊布洛芬的一或多個下伏塗層。因此，根據本文所述之一些實施例之伊布洛芬可具有第一功能性塗層及第二保護性塗層。Therefore, it has been found that the hydrophobic fuming silica and the glidant used as a functional coating of Ibuprofen to aid downstream processing can also be used to provide surrounding functional coating of Ibuprofen and/or part Or a hydrophobic barrier layer completely embedded in it. Specifically, the hydrophobic barrier layer formed by the hydrophobic fuming silica can protect the functionally coated ibuprofen during the preparation of the pharmaceutical suspension and other downstream processing of the functionally coated ibuprofen. One or more underlying coatings. Therefore, Ibuprofen according to some embodiments described herein may have a first functional coating and a second protective coating.

然而，本文提供之一些醫藥組合物及製備醫藥組合物之方法可不只包括第一塗層及第二塗層。舉例而言，一些醫藥組合物及其製備方法可包括三個、四個、五個、六個或更多個塗層。因此，不應狹義地解釋本文所用之術語「第一塗層」及「第二塗層」。如本文所用術語「第一塗層」係指伊布洛芬之功能性塗層，且「第二塗層」係指包含二氧化矽之保護性塗層。在一些實施例中，功能性塗覆之伊布洛芬可在「第一塗層」與「第二塗層」之間具有一或多個塗覆層。在一些實施例中，功能性塗覆之伊布洛芬可在伊布洛芬與「第一塗層」之間具有一或多個塗覆層。在一些實施例中，功能性塗覆之伊布洛芬可在「第二塗層」之頂部具有一或多個塗覆層。However, some of the pharmaceutical compositions and methods for preparing the pharmaceutical compositions provided herein may not only include the first coating and the second coating. For example, some pharmaceutical compositions and methods of making them may include three, four, five, six or more coatings. Therefore, the terms "first coating" and "second coating" used herein should not be interpreted narrowly. As used herein, the term "first coating" refers to a functional coating of ibuprofen, and "second coating" refers to a protective coating containing silicon dioxide. In some embodiments, the functionally coated ibuprofen may have one or more coating layers between the “first coating” and the “second coating”. In some embodiments, the functionally coated ibuprofen may have one or more coating layers between the ibuprofen and the "first coating." In some embodiments, the functionally coated ibuprofen may have one or more coating layers on top of the "second coating".

一旦製備功能性塗覆之伊布洛芬，可將其混合至基質/懸浮液溶液中以形成用於計量之醫藥懸浮液。將功能性塗覆之伊布洛芬混合至基質溶液/懸浮液中可侵蝕功能性塗覆之伊布洛芬之功能性塗層。在一些實施例中，為了使此侵蝕最小化，可使用疏水性發煙二氧化矽以形成包圍功能性塗覆之伊布洛芬及/或部分包埋及/或包埋於其中的第二塗覆層。Once the functionally coated ibuprofen is prepared, it can be mixed into the matrix/suspension solution to form a pharmaceutical suspension for metering. Mixing functionally coated ibprofen into the matrix solution/suspension can corrode the functional coating of functionally coated ibprofen. In some embodiments, in order to minimize this erosion, hydrophobic fuming silica may be used to form a second layer that surrounds the functionally coated ibuprofen and/or is partially embedded and/or embedded therein.涂层。 Coating.

然而，用疏水性發煙二氧化矽塗覆稍後將混合至基質溶液/懸浮液中的功能性塗覆之伊布洛芬(即，至少包含第一塗層之伊布洛芬，如上所述)並非自然直觀的。如上所述，為了產生根據本文所述實施例之口腔可分散醫藥組合物，將功能性塗覆之伊布洛芬混合至包含基質形成劑、結構形成劑及溶劑(通常為水)之基質溶液/懸浮液中，以形成醫藥懸浮液。然而，疏水材料自然地抵抗混合至基質溶液/懸浮液中。因此，可假定疏水性發煙二氧化矽將增加功能性塗覆之伊布洛芬及基質溶液/懸浮液之間之界面張力，從而增加將功能性塗覆之伊布洛芬併入基質溶液/懸浮液中之難度且潛在地引起醫藥懸浮液之相分離。However, the functionally coated ibuprofen (ie, ibuprofen containing at least the first coating layer) that will be mixed into the matrix solution/suspension later is coated with hydrophobic fuming silica, as described above Narration) is not natural and intuitive. As described above, in order to produce the orally dispersible pharmaceutical composition according to the embodiments described herein, the functionally coated ibuprofen is mixed into a matrix solution containing a matrix forming agent, a structure forming agent and a solvent (usually water) / Suspension to form a pharmaceutical suspension. However, hydrophobic materials naturally resist mixing into the matrix solution/suspension. Therefore, it can be assumed that the hydrophobic fuming silica will increase the interfacial tension between the functionally coated ibprofen and the matrix solution/suspension, thereby increasing the incorporation of the functionally coated ibprofen into the matrix solution / Difficulty in suspension and potentially cause phase separation of pharmaceutical suspensions.

有趣的是，已確定疏水性發煙二氧化矽可用於塗覆功能性塗覆之伊布洛芬，以保存第一功能性塗層而實質上不干擾功能性塗覆之伊布洛芬併入基質溶液/懸浮液中。如上所述，基質溶液/懸浮液中之疏水性物質、例如上述基質溶液/懸浮液中經疏水性發煙二氧化矽覆蓋之功能性塗覆之伊布洛芬，特徵性地展現疏水性物質與基質溶液/懸浮液之間之相對高的表面張力。因此，疏水性功能性塗覆之伊布洛芬與基質溶液/懸浮液之間之表面張力亦可能相對較高。Interestingly, it has been determined that the hydrophobic fuming silica can be used to coat the functionally coated ibuprofen to preserve the first functional coating without substantially interfering with the functionally coated ibuprofen. Into the matrix solution/suspension. As mentioned above, the hydrophobic substance in the matrix solution/suspension, such as the functionally coated Ibuprofen covered with hydrophobic fuming silica in the aforementioned matrix solution/suspension, exhibits a characteristic hydrophobic substance Relatively high surface tension with the matrix solution/suspension. Therefore, the surface tension between the hydrophobic functional coated ibprofen and the matrix solution/suspension may also be relatively high.

然而，如下文所論述，基質溶液/懸浮液可包含基質形成劑，例如明膠。一些基質形成劑(包括明膠)係溫和的表面活性劑，這意味著其可降低兩種物質之間之表面張力。因此，據信展現表面活性劑樣行為之基質形成劑可降低功能性塗覆之伊布洛芬與基質溶液/懸浮液之間之表面張力，此進而允許將功能性塗覆之伊布洛芬併入基質溶液/懸浮液中，而同時維持疏水性發煙二氧化矽塗覆層對功能性塗覆之伊布洛芬之第一功能性塗層的保護性質。包含疏水性發煙二氧化矽之此第二塗覆層可為功能性塗覆之伊布洛芬之下伏第一塗層提供疏水性屏障，以保護下伏第一塗層免於將功能性塗覆之伊布洛芬混合至醫藥懸浮液中所需的剪切力。藉由用包含疏水性發煙二氧化矽之疏水性屏障塗覆功能性塗覆之伊布洛芬，可保護下伏(第一)塗層免受侵蝕。此外，根據所述方法使用疏水性發煙二氧化矽可防止基質溶液/懸浮液穿透塗層到達伊布洛芬。However, as discussed below, the matrix solution/suspension may contain a matrix forming agent, such as gelatin. Some matrix formers (including gelatin) are mild surfactants, which means they can reduce the surface tension between the two substances. Therefore, it is believed that the matrix forming agent exhibiting surfactant-like behavior can reduce the surface tension between the functionally coated ibprofen and the matrix solution/suspension, which in turn allows the functionally coated ibprofen to be applied Incorporated into the matrix solution/suspension while maintaining the protective properties of the hydrophobic fuming silica coating layer to the functionally coated Ibuprofen first functional coating. This second coating layer containing hydrophobic fuming silica can provide a hydrophobic barrier for the underlying first coating of functionally coated Ibuprofen to protect the underlying first coating from functioning The shear force required to mix the sexually coated ibuprofen into the pharmaceutical suspension. By coating the functionally coated ibuprofen with a hydrophobic barrier containing hydrophobic fuming silica, the underlying (first) coating can be protected from erosion. In addition, the use of hydrophobic fuming silica according to the method prevents the matrix solution/suspension from penetrating the coating to reach Ibuprofen.

在正常之處理條件下，在無疏水性發煙二氧化矽塗覆層之情況下，在將功能性塗覆之伊布洛芬混合至基質溶液/懸浮液中所需之剪切力下，功能性塗覆之伊布洛芬之塗層會隨時間而被侵蝕。然而，自功能性塗覆之伊布洛芬首次混合至基質溶液/懸浮液中起，可存在兩小時或更多小時之「處理窗」，其中塗層可保持完整且其功能性可保持不受損。此「處理窗」之確切時間可變且可取決於功能性塗覆之伊布洛芬之各種組分之組成、基質溶液/懸浮液之組成、用於製備功能性塗覆之伊布洛芬之塗層之材料的量及/或伊布洛芬之物理化學性質。然而，利用具有包含發煙二氧化矽之第二塗層之功能性塗覆之伊布洛芬，此「處理窗」可延長。Under normal processing conditions, without the hydrophobic fuming silica coating, under the shear force required to mix the functionally coated ibuprofen into the matrix solution/suspension, The functional coating of ibuprofen will corrode over time. However, since the functionally coated Ibuprofen is first mixed into the matrix solution/suspension, there can be a "treatment window" of two or more hours, in which the coating can remain intact and its functionality can be maintained. Damaged. The exact time of this "treatment window" is variable and can depend on the composition of the various components of the functionally coated ibprofen, the composition of the matrix solution/suspension, and the preparation of the functionally coated ibprofen The amount of the coating material and/or the physical and chemical properties of Ibuprofen. However, with functionally coated Ibuprofen with a second coating containing fuming silica, this "treatment window" can be extended.

在一些實施例中，醫藥組合物或經塗覆之伊布洛芬可包含0.5至35 % w/w疏水性發煙二氧化矽。在一些實施例中，醫藥組合物或經塗覆之伊布洛芬可包含0.5至20 % w/w、0.5至10 % w/w或0.5至5 % w/w疏水性發煙二氧化矽。在一些實施例中，醫藥組合物或經塗覆之伊布洛芬可包含超過0.5 % w/w、超過1.0 % w/w、超過1.5 % w/w、超過2.0 % w/w、超過2.5 % w/w、超過3.0 % w/w、超過4.0 % w/w、超過5.0 % w/w、超過10 % w/w、超過15 % w/w、超過20 % w/w、超過25 % w/w或超過30 % w/w疏水性發煙二氧化矽。在一些實施例中，醫藥組合物或經塗覆之伊布洛芬可包含少於35 % w/w、少於25 % w/w、少於15 % w/w、少於10 % w/w、少於5.0 % w/w、少於4.0 % w/w、少於3.5 % w/w、少於3.0 % w/w、少於2.5 % w/w、少於2.0 % w/w、少於1.5 % w/w或少於1.0 % w/w疏水性發煙二氧化矽。疏水性發煙二氧化矽可為Aerosil R972二氧化矽(Degussa)、CAB-O-SIL EH-5二氧化矽(Cabot)、OX-50二氧化矽(Degussa)、COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan))、TS5二氧化矽(Cabot)及/或其他適宜類型之二氧化矽中之任一者。In some embodiments, the pharmaceutical composition or coated ibuprofen may comprise 0.5 to 35% w/w hydrophobic fuming silica. In some embodiments, the pharmaceutical composition or coated ibuprofen may comprise 0.5 to 20% w/w, 0.5 to 10% w/w, or 0.5 to 5% w/w hydrophobic fuming silica . In some embodiments, the pharmaceutical composition or coated ibuprofen may contain more than 0.5% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5 % w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w or more than 30% w/w hydrophobic fuming silica. In some embodiments, the pharmaceutical composition or coated ibuprofen may contain less than 35% w/w, less than 25% w/w, less than 15% w/w, less than 10% w/ w, less than 5.0% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, Less than 1.5% w/w or less than 1.0% w/w hydrophobic fuming silica. The hydrophobic fuming silica can be Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), TS5 silicon dioxide (Cabot) and/or other suitable types of silicon dioxide.

包含疏水性發煙二氧化矽之保護層的有效性可藉由量測醫藥懸浮液中之功能性塗覆之伊布洛芬隨時間之粒度來確定。若疏水性發煙二氧化矽有效保存塗層，則功能性塗覆之伊布洛芬之粒度可隨時間保持恆定或幾乎不降低。若無效，功能性塗覆之伊布洛芬之粒度可隨時間更顯著地減小。功能性塗覆之顆粒之粒度可使用雷射繞射、顆粒分析儀(例如Malvern Mastersizer)或分析細顆粒之任何其他適宜構件來量測。The effectiveness of the protective layer containing hydrophobic fuming silica can be determined by measuring the particle size of functionally coated ibuprofen in a pharmaceutical suspension over time. If the hydrophobic fuming silica effectively preserves the coating, the particle size of the functionally coated ibuprofen can remain constant or hardly decrease over time. If it is ineffective, the particle size of functionally coated ibuprofen can decrease more significantly over time. The particle size of the functionally coated particles can be measured using laser diffraction, a particle analyzer (such as Malvern Mastersizer), or any other suitable means for analyzing fine particles.

包含疏水性發煙二氧化矽之保護層的有效性亦可藉由對功能性塗覆之伊布洛芬執行溶解試驗來確定。若疏水性發煙二氧化矽有效保存塗層，則在溶解測試中，功能性塗覆之伊布洛芬隨時間之釋放量(例如，釋放百分比)將較慢。若無效，則功能性塗覆之伊布洛芬隨時間之釋放量將更大。功能性塗覆之顆粒之釋放量可使用溶解測試、分光光度分析儀(例如Pion MicroDISS Profiler)或用於執行溶解測試之任何其他適宜構件來量測。包含伊布洛芬之懸浮液之通氣最小化The effectiveness of the protective layer containing hydrophobic fuming silica can also be determined by performing a dissolution test on functionally coated ibuprofen. If the hydrophobic fuming silica effectively preserves the coating, in the dissolution test, the release amount (for example, the release percentage) of the functionally coated ibuprofen over time will be slower. If it is ineffective, the release of functionally coated Ibuprofen over time will be greater. The release amount of the functionally coated particles can be measured using a dissolution test, a spectrophotometric analyzer (such as Pion MicroDISS Profiler) or any other suitable means for performing the dissolution test. Minimize ventilation of suspensions containing Ibuprofen

本文提供之實施例可包括向基質溶液/懸浮液中添加包含萜烯及/或萜品醇之化學化合物。具體地，本文提供之醫藥懸浮液之實施例可包括包含萜烯及/或萜品醇之液體矯味劑。在一些實施例中，液體矯味劑可包括萜烯檸檬烯。當將懸浮液注入模具中時，特定化學化合物且具體地包含檸檬烯之液體矯味劑之添加，可使懸浮液之通氣最小化，增加懸浮液之均質性，且改良計量重量之準確度。如本文所用之「計量重量準確度」及相關術語係指將醫藥懸浮液準確地分配至預成形模具中之能力。經計量之醫藥懸浮液之計量重量準確度可取決於多個變量，包括但不限於均勻性、黏度、化學組分、計量儀器等。The embodiments provided herein may include the addition of chemical compounds containing terpenes and/or terpineol to the matrix solution/suspension. Specifically, embodiments of the pharmaceutical suspensions provided herein may include liquid flavoring agents containing terpenes and/or terpineol. In some embodiments, the liquid flavoring agent may include the terpene limonene. When the suspension is injected into the mold, the addition of specific chemical compounds and specifically a liquid flavoring agent containing limonene can minimize the aeration of the suspension, increase the homogeneity of the suspension, and improve the accuracy of weighing. As used herein, "metering weight accuracy" and related terms refer to the ability to accurately dispense a pharmaceutical suspension into a preform mold. The accuracy of the metered weight of the medicinal suspension may depend on multiple variables, including but not limited to uniformity, viscosity, chemical composition, metering instruments, etc.

如上所述，由於醫藥懸浮液之高黏度，防通氣及/或最小化通氣之傳統機械方式尚未發現有成功的。舉例而言，對醫藥懸浮液施加真空可引起懸浮液之高度上升，此乃因黏性懸浮液「抓握」在夾帶之空氣上。揮發性調配物組分亦可在真空處理期間損失。此外，傳統防通氣劑(例如乙醇或西甲矽油乳液)類似地不能有效地對懸浮液防通氣。As mentioned above, due to the high viscosity of pharmaceutical suspensions, traditional mechanical methods for preventing ventilation and/or minimizing ventilation have not been found to be successful. For example, applying a vacuum to a pharmaceutical suspension can cause the height of the suspension to rise. This is because the viscous suspension "grips" on the entrained air. Volatile formulation components can also be lost during vacuum processing. In addition, traditional anti-aeration agents (such as ethanol or simethicone emulsion) similarly cannot effectively prevent aeration of suspensions.

因此，已發現，當將疏水性經塗覆之伊布洛芬混合至基質溶液/懸浮液中時，一些化合物且具體而言包含萜烯及/或萜品醇(例如檸檬烯)之液體矯味劑可使醫藥懸浮液之通氣最小化。藉由使通氣最小化，疏水性經塗覆之伊布洛芬更有效及高效地分散在整個醫藥懸浮液中。此增加之分散可增加醫藥懸浮液之均質性、計量重量準確度以及最終產品之含量均勻性。Therefore, it has been found that when the hydrophobic coated ibuprofen is mixed into the matrix solution/suspension, some compounds and specifically liquid flavoring agents containing terpenes and/or terpineols (such as limonene) The ventilation of the pharmaceutical suspension can be minimized. By minimizing ventilation, the hydrophobic coated ibuprofen is more effectively and efficiently dispersed throughout the pharmaceutical suspension. This increased dispersion can increase the homogeneity of the pharmaceutical suspension, the accuracy of metering weight, and the content uniformity of the final product.

如上所述，將疏水性經塗覆之伊布洛芬混合至基質溶液/懸浮液中可在液體中產生夾帶之空氣或氣泡。由於經塗覆之伊布洛芬係疏水的，故其通常對基質溶液/懸浮液具有低親和力。因此，疏水性經塗覆之伊布洛芬並非容易地與基質溶液/懸浮液締合及分散至基質溶液/懸浮液中，而是較佳與夾帶之空氣締合。在許多流體中，氣泡通常行進至流體之表面且在上方之空氣中消失。然而，由於疏水性經塗覆之伊布洛芬對夾帶之空氣具有親和力，故疏水性經塗覆之伊布洛芬「抓握」在氣泡上，從而防止其進行至表面並釋放至流體上方之空氣中。此使得醫藥懸浮液變得通氣。醫藥懸浮液之通氣可引起相分離，且因此引起不均質懸浮液。在暴露於由計量幫浦引入之剪切力時，相分離亦可變得加劇。當通過計量幫浦時，不均質醫藥懸浮液可導致泵滯塞，從而導致計量重量不準確且整個最終產品缺乏均勻性以及由於停機而導致生產效率差。As mentioned above, mixing the hydrophobic coated ibuprofen into the matrix solution/suspension can generate entrained air or bubbles in the liquid. Since the coated ibuprofen is hydrophobic, it usually has a low affinity for the matrix solution/suspension. Therefore, the hydrophobic coated ibuprofen is not easily associated with and dispersed into the matrix solution/suspension, but is preferably associated with entrained air. In many fluids, air bubbles usually travel to the surface of the fluid and disappear in the air above. However, because the hydrophobic coated Ibuprofen has an affinity for entrained air, the hydrophobic coated Ibuprofen "grabs" on the bubbles, preventing them from reaching the surface and releasing onto the fluid. In the air. This makes the pharmaceutical suspension aerated. Aeration of pharmaceutical suspensions can cause phase separation, and therefore cause inhomogeneous suspensions. The phase separation can also become exacerbated when exposed to the shear forces introduced by the metering pump. When passing the metering pump, the inhomogeneous pharmaceutical suspension can cause pump blockage, resulting in inaccurate metering weight and lack of uniformity in the entire final product, and poor production efficiency due to downtime.

另外，由於疏水性經塗覆之伊布洛芬之高負載(即，多達50 wt. %疏水性經塗覆之伊布洛芬)，包含疏水性經塗覆之伊布洛芬之醫藥懸浮液可具有高黏度。如上所述，在將疏水性經塗覆之伊布洛芬線上混合至懸浮液中期間，將空氣夾帶至醫藥懸浮液中甚至可進一步增加醫藥懸浮液之黏度。因此，不僅懸浮液之相分離及不均質性不利地影響最終產品之計量重量準確度及均勻性，且增加之黏度亦不利地影響最終產品之計量重量準確度及均勻性。In addition, due to the high loading of hydrophobic coated ibprofen (ie, as much as 50 wt.% hydrophobic coated ibprofen), medicines including hydrophobic coated ibprofen The suspension can have a high viscosity. As mentioned above, the entrainment of air into the pharmaceutical suspension during the mixing of the hydrophobic coated ibuprofen wire into the suspension can even further increase the viscosity of the pharmaceutical suspension. Therefore, not only the phase separation and heterogeneity of the suspension adversely affect the accuracy and uniformity of the final product's weight, but the increased viscosity also adversely affects the accuracy and uniformity of the final product's weight.

有趣的是，已發現某些化學化合物在添加至基質溶液/懸浮液中時可使包含疏水性經塗覆之伊布洛芬之醫藥懸浮液之通氣最小化。具體而言，根據本文提供之一些實施例之包含萜烯及/或萜品醇之化學化合物可使由疏水性經塗覆之伊布洛芬線上混合至基質溶液/懸浮液中引起之醫藥懸浮液中夾帶之空氣量最小化。舉例而言，包含含有萜烯及/或萜品醇之液體矯味劑之懸浮液即使以相對低之濃度亦可使醫藥懸浮液之通氣最小化。具體地，已發現，包含一或多種包含檸檬烯之液體矯味劑之基質溶液/懸浮液可使疏水性經塗覆之伊布洛芬之線上混合期間的醫藥懸浮液中之通氣最小化。包括萜烯及萜品醇之其他化學化合物亦已顯示在使醫藥懸浮液之通氣最小化方面係成功的。舉例而言，包括萜烯(例如檸檬烯、香芹酮、葎草烯、紫杉二烯及角鯊烯)之化學化合物可適於使醫藥懸浮液之通氣最小化。萜品醇亦可為適宜防通氣劑。在一些實施例中，純萜烯及/或純萜品醇可用作防通氣劑。在一些實施例中，包含萜烯及/或萜品醇之液體矯味劑可用作防通氣劑。在一些實施例中，包含萜烯及/或萜品醇之其他適宜化學化合物可用作防通氣劑。Interestingly, it has been found that certain chemical compounds, when added to the matrix solution/suspension, can minimize the aeration of pharmaceutical suspensions containing hydrophobic coated ibuprofen. Specifically, chemical compounds containing terpenes and/or terpineols according to some embodiments provided herein can cause pharmaceutical suspensions caused by in-line mixing of hydrophobic coated ibuprofen into a matrix solution/suspension The amount of air entrained in the liquid is minimized. For example, a suspension containing a liquid flavoring agent containing terpene and/or terpineol can minimize aeration of the pharmaceutical suspension even at a relatively low concentration. Specifically, it has been found that a matrix solution/suspension containing one or more liquid flavoring agents containing limonene can minimize ventilation in the pharmaceutical suspension during in-line mixing of hydrophobic coated ibprofen. Other chemical compounds including terpenes and terpineol have also been shown to be successful in minimizing the aeration of pharmaceutical suspensions. For example, chemical compounds including terpenes (such as limonene, carvone, humulene, taxadiene, and squalene) may be suitable for minimizing aeration of pharmaceutical suspensions. Terpineol can also be a suitable anti-ventilation agent. In some embodiments, pure terpene and/or pure terpineol can be used as an anti-ventilation agent. In some embodiments, liquid flavoring agents containing terpenes and/or terpineol can be used as anti-ventilating agents. In some embodiments, other suitable chemical compounds containing terpenes and/or terpineol can be used as anti-ventilating agents.

一些包含萜烯及/或萜品醇之化學化合物、例如一些液體矯味劑所面臨之一個挑戰係其往往係相對油性。與習用油及水一樣，該等油性化學化合物可能不容易分散至基質溶液/懸浮液中。然而，如下文所論述，根據本文實施例之基質溶液/懸浮液可包括明膠作為基質形成劑。明膠本身係溫和的表面活性劑。表面活性劑可降低兩種材料之間之表面張力。因此，在一些實施例中，基質溶液/懸浮液之明膠可降低油性化學化合物與基質溶液/懸浮液之間之表面張力。此可允許將油性化合物(例如液體矯味劑)充分併入基質溶液/懸浮液中。One challenge faced by some chemical compounds containing terpenes and/or terpineol, such as some liquid flavoring agents, is that they tend to be relatively oily. Like conventional oil and water, these oily chemical compounds may not easily disperse into the matrix solution/suspension. However, as discussed below, the matrix solution/suspension according to the embodiments herein may include gelatin as a matrix forming agent. Gelatin itself is a mild surfactant. Surfactants can reduce the surface tension between two materials. Therefore, in some embodiments, the gelatin of the matrix solution/suspension can reduce the surface tension between the oily chemical compound and the matrix solution/suspension. This can allow oily compounds (e.g. liquid flavors) to be fully incorporated into the base solution/suspension.

在正常處理條件下，在不使用包含萜烯及/或萜品醇之化學化合物之情況下，由於將疏水性經塗覆之伊布洛芬混合至基質溶液/懸浮液中以形成醫藥懸浮液所需之剪切力，疏水性經塗覆之伊布洛芬之塗層隨時間被侵蝕。然而，存在兩個或更多個小時之「處理窗」，其中塗層保持顯著之功能性。對於每一產品，此「處理窗」之確切時間可變，且可取決於疏水性經塗覆之伊布洛芬之組分之組成、基質溶液/懸浮液之組成、用於製備疏水性經塗覆之伊布洛芬之材料的量、伊布洛芬之物理化學性質及/或混合條件。不幸的是，在包含萜烯及/或萜品醇之化學化合物之存在下，由於該等化學化合物與疏水性經塗覆之伊布洛芬之塗層之間之相互作用，此「處理窗」可顯著減小。該等相互作用可損害塗層之功能性質。舉例而言，液體矯味劑與疏水性經塗覆之伊布洛芬之塗層之間之相互作用可損害塗層之任何掩味功能。亦即，已發現，存在臨限值化學化合物(即液體矯味劑)濃度，低於該濃度，化學化合物不會顯著損害塗層，但「處理窗」沒有減小太多以至於疏水性經塗覆之伊布洛芬之塗層會顯著侵蝕。因此，包含萜烯及/或萜品醇之化學化合物之此最佳量充分地使醫藥懸浮液之通氣最小化，從而產生可準確地計量至模具中以產生均勻之最終產品的均質醫藥懸浮液。Under normal processing conditions, without using chemical compounds containing terpene and/or terpineol, the hydrophobic coated ibuprofen is mixed into the matrix solution/suspension to form a pharmaceutical suspension With the required shearing force, the hydrophobic coated ibuprofen coating is eroded over time. However, there is a "treatment window" of two or more hours, in which the coating retains significant functionality. For each product, the exact time of this "treatment window" is variable and can depend on the composition of the hydrophobically coated ibuprofen components, the composition of the matrix solution/suspension, and the preparation of hydrophobic The amount of the material of Ibuprofen coated, the physicochemical properties of Ibuprofen and/or the mixing conditions. Unfortunately, in the presence of chemical compounds containing terpene and/or terpineol, due to the interaction between these chemical compounds and the hydrophobic coated ibuprofen coating, this "treatment window" "Can be significantly reduced. These interactions can damage the functional properties of the coating. For example, the interaction between the liquid flavoring agent and the hydrophobic coated ibuprofen coating can impair any taste masking function of the coating. That is, it has been found that there is a threshold chemical compound (ie liquid flavoring agent) concentration, below which the chemical compound will not significantly damage the coating, but the "treatment window" is not reduced so much that the hydrophobicity is coated The coating of Ibuprofen will corrode significantly. Therefore, this optimal amount of chemical compounds containing terpene and/or terpineol sufficiently minimizes the aeration of the pharmaceutical suspension, thereby producing a homogeneous pharmaceutical suspension that can be accurately metered into the mold to produce a uniform final product .

另外，包含萜烯及/或萜品醇之化學化合物且具體地包含檸檬烯之液體矯味劑具有降低醫藥懸浮液之凝固點的潛能，這可導致藉由冷凍乾燥進一步處理之產品的熔融缺陷。具體而言，檸檬烯具有-74℃之凝固點。然而，在製備揭示之產品期間未觀察到熔融缺陷，且因此至少一些包含萜烯及/或萜品醇之化學化合物不影響醫藥懸浮液，使得下游冷凍及冷凍乾燥過程步驟受到不利影響。認為在目前情況下不存在熔融缺陷係由於懸浮液之高固體含量，此即使在凝固點降低劑(即，檸檬烯)之存在下亦有助於維持產品之結構。In addition, chemical compounds containing terpene and/or terpineol, and in particular liquid flavoring agents containing limonene, have the potential to lower the freezing point of pharmaceutical suspensions, which can lead to melting defects in products further processed by freeze drying. Specifically, limonene has a freezing point of -74°C. However, no melting defects were observed during the preparation of the disclosed product, and therefore at least some chemical compounds containing terpenes and/or terpineol do not affect the pharmaceutical suspension, so that the downstream freezing and freeze-drying process steps are adversely affected. It is believed that the absence of melting defects in the current situation is due to the high solid content of the suspension, which helps maintain the structure of the product even in the presence of the freezing point depressant (ie, limonene).

根據本文所述之實施例之基質溶液/懸浮液組合物可包括基質形成劑、結構形成劑、防通氣劑、黏度調節劑及/或溶劑。The matrix solution/suspension composition according to the embodiments described herein may include a matrix forming agent, a structure forming agent, an anti-ventilating agent, a viscosity regulator, and/or a solvent.

在一些實施例中，基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中包含萜烯及/或萜品醇(即，防通氣劑)之化學化合物的量可為0.001至5.0 % w/w。在一些實施例中，基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中包含萜烯及/或萜品醇(即，防通氣劑)之化學化合物的量可為1-5 % w/w、1-4% w/w、1-3% w/w、1-2 % w/w、0.05至3.0 % w/w、0.1至2.0 % w/w或0.5至1.0 % w/w。在一些實施例中，超過0.001 % w/w、超過0.01 % w/w、超過0.05 % w/w、超過0.1 % w/w、超過0.3 % w/w、超過0.5 % w/w、超過0.8 % w/w、超過1.0 % w/w、超過1.5 % w/w、超過2.0 % w/w、超過2.5 % w/w、超過3.0 % w/w、超過3.5 % w/w、超過4.0 % w/w或超過4.5 % w/w之包含萜烯及/或萜品醇(即，防通氣劑)之化學化合物在基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中。在一些實施例中，少於5.0 % w/w、少於4.5 % w/w、少於4.0 % w/w、少於3.5 % w/w、少於3.0 % w/w、少於2.5 % w/w、少於2.0 % w/w、少於1.5 % w/w、少於1.0 % w/w、少於0.8 % w/w、少於0.6 % w/w、少於0.3 % w/w或少於0.1 % w/w之包含萜烯及/或萜品醇(即，防通氣劑)之化學化合物在基質溶液/懸浮液、醫藥懸浮液或醫藥組合物中。在一些實施例中，適宜防通氣劑可包括橙味矯味劑、草莓味矯味劑、薄荷味矯味劑、樹莓味矯味劑、甘草味矯味劑、橙味矯味劑、檸檬味矯味劑、酸檸檬味矯味劑、葡萄柚味矯味劑、焦糖味矯味劑、香草味矯味劑、櫻桃味矯味劑、葡萄味矯味劑、混合果實味矯味劑、什錦水果味矯味劑或其任一組合。最小化黏聚實例In some embodiments, the amount of chemical compounds containing terpene and/or terpineol (ie, anti-ventilating agent) in the matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition may be 0.001 to 5.0% w/w . In some embodiments, the amount of chemical compounds containing terpene and/or terpineol (ie, anti-ventilating agent) in the matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition can be 1-5% w/w , 1-4% w/w, 1-3% w/w, 1-2% w/w, 0.05 to 3.0% w/w, 0.1 to 2.0% w/w or 0.5 to 1.0% w/w. In some embodiments, more than 0.001% w/w, more than 0.01% w/w, more than 0.05% w/w, more than 0.1% w/w, more than 0.3% w/w, more than 0.5% w/w, more than 0.8 % w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than 3.0% w/w, more than 3.5% w/w, more than 4.0% w/w or more than 4.5% w/w of chemical compounds containing terpene and/or terpineol (ie, anti-ventilating agent) in a matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition. In some embodiments, less than 5.0% w/w, less than 4.5% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, less than 1.0% w/w, less than 0.8% w/w, less than 0.6% w/w, less than 0.3% w/ w or less than 0.1% w/w of chemical compounds containing terpene and/or terpineol (ie, anti-ventilating agent) in a matrix solution/suspension, pharmaceutical suspension or pharmaceutical composition. In some embodiments, suitable anti-ventilation agents may include orange flavoring agents, strawberry flavoring agents, mint flavoring agents, raspberry flavoring agents, licorice flavoring agents, orange flavoring agents, lemon flavoring agents, lime flavoring agents. Flavor correctives, grapefruit flavor correctives, caramel flavor correctives, vanilla flavor correctives, cherry flavor correctives, grape flavor correctives, mixed fruit flavor correctives, assorted fruit flavor correctives or any combination thereof. Minimize Cohesion Examples

實施若干試驗以評價藉由篩分自經塗覆之伊布洛芬中去除過量塗覆材料之有效性，且最佳化塗覆比及計量比。在各種條件下量測含有各種經塗覆之伊布洛芬之醫藥組合物之崩解時間，以研究篩分過量塗覆材料之效應。可合理地假設，去除過量塗料可使塗覆材料之黏聚最小化。最佳化塗覆及計量比亦可有助於使塗覆材料之黏聚最小化。使黏聚量最小化進而可有助於維持醫藥組合物及經塗覆之伊布洛芬之期望崩解時間及/或溶解速率。因此，在以下實例中，崩解時間用作評價黏聚量之度量。在一些實施例中，50℃加速分解數據可指示未篩分之過量塗覆材料的存在。Several tests were performed to evaluate the effectiveness of removing excess coating material from the coated ibuprofen by sieving, and to optimize the coating ratio and metering ratio. The disintegration time of pharmaceutical compositions containing various coated ibuprofen was measured under various conditions to study the effect of screening excessive coating materials. It is reasonable to assume that removing the excess paint can minimize the adhesion of the coating material. Optimizing the coating and metering ratio can also help minimize the adhesion of the coating material. Minimizing the amount of cohesion in turn can help maintain the desired disintegration time and/or dissolution rate of the pharmaceutical composition and coated ibuprofen. Therefore, in the following examples, the disintegration time is used as a metric to evaluate the amount of cohesion. In some embodiments, the 50°C accelerated decomposition data can indicate the presence of unsieved excess coating material.

另外，為以下實例提供塗覆比及計量比資訊。塗覆比係指塗覆材料之量對未經塗覆之伊布洛芬之量的比率。計量比係指經塗覆之伊布洛芬之量對包含所有非活性成份之基質溶液/懸浮液之量的比率。In addition, provide coating ratio and metering ratio information for the following examples. The coating ratio refers to the ratio of the amount of coated material to the amount of uncoated ibuprofen. The metering ratio refers to the ratio of the amount of coated ibuprofen to the amount of matrix solution/suspension containing all inactive ingredients.

實例 1 ：用巴西棕櫚蠟以26:74之塗覆比塗覆伊布洛芬。使用40:60之計量比製備冷凍乾燥之錠劑。測試四個單獨批次之錠劑-在2個月時段內測試批次1-3，且在6個月時段內測試批次4。該等批次之錠劑各自在25℃/60%RH、30℃/65% RH及40℃/75% RH之ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use)穩定性條件下測試，且在一個月及兩個月時對批次1、2及3取樣。另外，將每一批次暴露於50℃應力條件以提供每一研究之兩週及四週時之加速數據。下表1提供經塗覆之伊布洛芬之兩個月研究之批次1-3的崩解時間數據。批次批號強度初始DT 2週 4週 1個月 1個月 1個月 2個月 2個月 2個月 50℃ 50℃ 25℃/ 60%RH 30℃/ 65%RH 40℃/ 75%RH 25℃/ 60%RH 30℃/ 65%RH 40℃/ 75%RH 1 Z3876/128 400 MG ＜ 2 s ＜ 4 s ＜ 10 s ＜ 4 s ＜ 4 s ＜ 4 s ＜ 3 s ＜ 4 s ＜ 7 s 2 Z4630/97 50 MG ＜ 2 s ＜ 4 s ＜ 7 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 15 s 3 Z4630/101 50 MG ＜ 3 s ＜ 3 s ＜ 4 s ＜ 1 s ＜ 2 s ＜ 3 s ＜ 2 s ＜ 2 s ＜ 2 s 表 1. 巴西棕櫚蠟 ( 計量比 40:60) (2 個月研究 ) Example 1 : Ibuprofen was coated with carnauba wax at a coating ratio of 26:74. Prepare freeze-dried lozenges using a 40:60 metering ratio. Four separate batches of lozenges were tested-batches 1-3 were tested in a 2-month period and batch 4 was tested in a 6-month period. These batches of tablets were tested under ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) stability conditions at 25°C/60%RH, 30°C/65% RH and 40°C/75% RH. , And sample batches 1, 2 and 3 at one and two months. In addition, each batch was exposed to 50°C stress conditions to provide acceleration data at two and four weeks of each study. Table 1 below provides disintegration time data for batches 1-3 of the two-month study of coated Ibuprofen. batch batch number strength Initial DT Two weeks 4 weeks 1 month 1 month 1 month 2 months 2 months 2 months 50℃ 50℃ 25℃/ 60%RH 30℃/65%RH 40°C/ 75%RH 25℃/ 60%RH 30℃/65%RH 40°C/ 75%RH 1 Z3876/128 400 MG ＜ 2 s ＜ 4 s ＜ 10 s ＜ 4 s ＜ 4 s ＜ 4 s ＜ 3 s ＜ 4 s ＜ 7 s 2 Z4630/97 50 MG ＜ 2 s ＜ 4 s ＜ 7 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 15 s 3 Z4630/101 50 MG ＜ 3 s ＜ 3 s ＜ 4 s ＜ 1 s ＜ 2 s ＜ 3 s ＜ 2 s ＜ 2 s ＜ 2 s Table 1. Carnauba wax ( measurement ratio 40:60) (2 months study )

在伊布洛芬塗覆後，批次2之經塗覆之伊布洛芬之篩分很差。篩分之經塗覆之伊布洛芬之顯微鏡檢查(圖4B)顯示存在過量未結合之塗覆材料。篩分之經塗覆之伊布洛芬之顯微鏡檢查亦顯示伊布洛芬之塗覆很差。如表1最後一欄中所示，此批次在40℃/75% RH穩定性測試條件下兩個月後展現顯著更長之崩解時間。(初始崩解時間小於兩秒，且兩個月時之崩解時間幾乎為15秒)。因此，此結果支持以下假說：由於在儲存期間未結合之塗覆材料之黏聚，在藥物產品中存在過量之未結合之塗覆材料導致崩解時間隨時間延長(隨著醫藥產品老化)。After Ibuprofen was coated, the sieving of the coated Ibuprofen of Batch 2 was poor. Microscopic examination of the sieved coated ibuprofen (Figure 4B) showed the presence of excess unbound coating material. Microscopic examination of the sieved coated Ibuprofen also showed poor coating of Ibuprofen. As shown in the last column of Table 1, this batch exhibited a significantly longer disintegration time after two months under the 40°C/75% RH stability test conditions. (The initial disintegration time is less than two seconds, and the disintegration time at two months is almost 15 seconds). Therefore, this result supports the hypothesis that due to the cohesion of the unbound coating material during storage, the presence of an excessive amount of unbound coating material in the drug product causes the disintegration time to extend over time (as the drug product ages).

相反，在伊布洛芬塗覆後，充分篩分批次3之經塗覆之伊布洛芬。篩分之經塗覆之伊布洛芬之顯微鏡檢查(圖4C)顯示伊布洛芬經充分塗覆，此乃因不存在未結合之塗覆材料。對於任何ICH穩定性條件，該批次樣品之崩解時間在兩個月之時段內變化極小。(在整個兩個月之研究中崩解時間在約一秒與約三秒之間波動)。此支持以下假說：藉由例如篩分使過量之未結合之塗覆材料之存在最小化將有助於防止在放置儲存時、具體而言在較高溫度下隨時間推移塗覆材料在醫藥產品中之黏聚。In contrast, after Ibuprofen was coated, batch 3 of the coated Ibuprofen was thoroughly screened. The microscopic examination of the sieved coated ibuprofen (Figure 4C) showed that the ibuprofen was fully coated, because there was no unbound coating material. For any ICH stability conditions, the disintegration time of this batch of samples changes very little within a two-month period. (The disintegration time fluctuated between about one second and about three seconds during the entire two-month study). This supports the hypothesis that minimizing the presence of excess unbound coating material by, for example, sieving will help prevent the coating material from becoming in the pharmaceutical product over time during storage, specifically at higher temperatures Cohesion in.

在伊布洛芬塗覆後，對批次1之經塗覆之伊布洛芬進行篩分。對於初始時間數據點，批次1與批次2及3相比展現小於2秒之類似崩解時間。然而，在40℃/75% RH穩定性測試條件下兩個月後，崩解時間增加至約7秒或更短。當在50℃下儲存4週時，崩解時間增加至約10秒或更短。此表明該批次之篩分製程未顯著去除過量塗覆材料，因此存在殘餘未結合之塗覆材料。批次2經歷甚至更多之未結合之塗料，且在儲存時比批次1更大程度地黏聚。篩分之經塗覆之伊布洛芬之顯微鏡檢查(圖4A)顯示伊布洛芬顆粒經殘餘量之存在之未結合之塗覆材料適度良好地塗覆。After Ibuprofen was coated, batch 1 of the coated Ibuprofen was screened. For the initial time data point, batch 1 exhibited a similar disintegration time of less than 2 seconds compared to batches 2 and 3. However, after two months under the 40°C/75% RH stability test conditions, the disintegration time increased to about 7 seconds or less. When stored at 50°C for 4 weeks, the disintegration time increased to about 10 seconds or less. This indicates that the screening process of this batch did not significantly remove excess coating material, so there is residual unbound coating material. Batch 2 experienced even more unbound paint and cohesive to a greater degree than batch 1 during storage. Microscopic examination of the sieved coated Ibuprofen (Figure 4A) showed that the Ibuprofen particles were moderately well coated with the presence of residual amounts of unbound coating material.

下表2顯示經塗覆之伊布洛芬(即批次4)之六個月研究之崩解時間數據。批次批號強度初始 2 週 4 週 1個月 1個月 1個月 3個月 3個月 3個月 6個月 6個月 6個月 50℃ 50℃ 25 ℃ /60 % RH 30 ℃ /65 % RH 40 ℃ /75 % RH 25 ℃ /60 % RH 30 ℃ /65 % RH 40 ℃ /75 % RH 25 ℃ /60 % RH 30 ℃ /65 % RH 40 ℃ /75 % RH 4 Z3876 /131 200 MG ＜5 s ＜20 s ＜13 s ＜5 s ＜4 s ＜5 s ＜4 s ＜3 s ＜4 s ＜2 s ＜2 s ＜2 s 表 2. 巴西棕櫚蠟 ( 計量比 40:60) (6 個月研究 ) Table 2 below shows the disintegration time data of the coated ibuprofen (i.e. batch 4) for a six-month study. batch batch number strength initial Two weeks 4 weeks 1 month 1 month 1 month 3 months 3 months 3 months 6 months 6 months 6 months 50℃ 50℃ 25 ℃ /60% RH 30 ℃ /65% RH 40 ℃ /75% RH 25 ℃ /60% RH 30 ℃ /65% RH 40 ℃ /75% RH 25 ℃ /60% RH 30 ℃ /65% RH 40 ℃ /75% RH 4 Z3876 /131 200 MG ＜5 s ＜20 s ＜13 s ＜5 s ＜4 s ＜5 s ＜4 s ＜3 s ＜4 s ＜2 s ＜2 s ＜2 s Table 2. Carnauba wax ( measurement ratio 40:60) (6 months study )

在伊布洛芬塗覆後，對批次4之經塗覆之伊布洛芬進行篩分。表2之批次4在整個六個月研究之持續時間內未顯示崩解時間之很大變化。批次4之初始崩解時間為約五秒，且25℃/60% RH樣品之最終崩解時間為約兩秒；30℃/65% RH樣品為約兩秒，且40℃/75% RH樣品為約兩秒。然而，當在50℃下儲存時，觀察到增加。由於在40℃及更低之溫度下儲存之錠劑中未觀察到增加，此表明篩分已去除大部分未結合之過量塗覆材料，但具有足夠之殘餘量，當將錠劑置於50℃時，該殘餘量會黏聚。顯微鏡檢查(圖4D)顯示，篩分之經塗覆之伊布洛芬顯示伊布洛芬經殘餘量之未結合之塗覆材料適度良好地塗覆。After Ibuprofen was coated, batch 4 of the coated Ibuprofen was screened. Batch 4 of Table 2 did not show a significant change in disintegration time over the duration of the entire six-month study. The initial disintegration time of batch 4 is about five seconds, and the final disintegration time of the 25℃/60% RH sample is about two seconds; the 30℃/65% RH sample is about two seconds, and the 40℃/75% RH The sample is about two seconds. However, when stored at 50°C, an increase was observed. Since no increase was observed in the lozenges stored at temperatures of 40°C and lower, this indicates that sieving has removed most of the unbound excess coating material, but there is sufficient residual amount, when the lozenges are placed at 50 At ℃, the residual amount will cohesive. Microscopic examination (Figure 4D) showed that the sieved coated ibuprofen showed that ibuprofen was coated moderately well with the residual amount of unbound coating material.

實例 2 ：用Sasol (合成)蠟以26:74之理論塗覆比塗覆伊布洛芬。塗覆後，對經塗覆之伊布洛芬進行篩分。使用40:60之計量比產生冷凍乾燥之錠劑且在兩個月內進行測試。伊布洛芬強度為200 mg。在25℃/60% RH、30℃/65% RH及40℃/75% RH之ICH穩定性條件下測試每一批次。另外，將樣品暴露於50℃應力條件以提供研究期間之兩週及四週時之加速數據。下表3提供經塗覆之伊布洛芬之40:60計量比之兩個月之研究的崩解時間數據。篩分之經塗覆之伊布洛芬之顯微鏡檢查(圖4E)顯示伊布洛芬經少量未結合之塗覆材料適度良好地塗覆。批次批號初始DT 2週 4週 1個月 1個月 1個月 2個月 2個月 2個月 50℃ 50℃ 25℃/ 60%RH 30℃/ 65%RH 40℃/ 75%RH 25℃/ 60%RH 30℃/ 65%RH 40℃/ 75%RH 5 Z3876/138 ＜ 3 s ＜ 3 s ＜4 s ＜ 2 s ＜ 2 s ＜5 s ＜4 s ＜4 s ＜4 s 表 3. Sasol 蠟 ( 計量比 40:60) 伊布洛芬強度： 200 mg Example 2 : Ibuprofen was coated with Sasol (synthetic) wax with a theoretical coating ratio of 26:74. After coating, the coated ibuprofen was screened. A 40:60 metering ratio was used to produce freeze-dried lozenges and tested within two months. The strength of Ibuprofen is 200 mg. Test each batch under the ICH stability conditions of 25℃/60% RH, 30℃/65% RH and 40℃/75% RH. In addition, the samples were exposed to 50°C stress conditions to provide acceleration data at two and four weeks during the study period. Table 3 below provides the disintegration time data of the two-month study of the 40:60 metering ratio of coated Ibuprofen. Microscopic examination of the sieved coated Ibuprofen (Figure 4E) showed that Ibuprofen was moderately well coated with a small amount of unbound coating material. batch batch number Initial DT Two weeks 4 weeks 1 month 1 month 1 month 2 months 2 months 2 months 50℃ 50℃ 25℃/ 60%RH 30℃/65%RH 40°C/ 75%RH 25℃/ 60%RH 30℃/65%RH 40°C/ 75%RH 5 Z3876/138 ＜ 3 s ＜ 3 s ＜4 s ＜ 2 s ＜ 2 s ＜5 s ＜4 s ＜4 s ＜4 s Table 3. Sasol wax ( dosing ratio 40:60) Ibuprofen strength: 200 mg

表3之批次5未顯示在研究之兩個月期間崩解時間發生顯著變化，在50℃加速條件下亦未發生變化。具體地，批次5之初始崩解時間為約三秒，且對於所有三種ICH穩定性條件(25℃/60% RH、30℃/65% RH及40℃/75% RH)在兩個月時之崩解時間為約四秒。50℃加速條件下兩週時之崩解時間為約三秒，且4週時為約四秒。基於50℃數據，可存在少量殘餘之未結合之過量塗覆材料。若存在，此少量未結合之過量塗覆材料不會在儲存時引起顯著量之黏聚，此乃因崩解時間即使增加亦不會增加太多。此與使用不同蠟之實例1中之批次3相當。該2個實例展現，若藉由篩分有效去除未結合之過量塗覆材料，則可最小化或防止在儲存時、具體而言在較高溫度下及在延長儲存時段後醫藥產品中之塗覆材料之黏聚。Batch 5 of Table 3 did not show a significant change in disintegration time during the two months of the study, nor did it change under accelerated conditions at 50°C. Specifically, the initial disintegration time of batch 5 is about three seconds, and for all three ICH stability conditions (25°C/60% RH, 30°C/65% RH, and 40°C/75% RH) within two months The disintegration time is about four seconds. The disintegration time under 50°C accelerated conditions was about three seconds at two weeks, and about four seconds at 4 weeks. Based on the 50°C data, there may be a small amount of residual unbound excess coating material. If present, this small amount of unbound excess coating material will not cause a significant amount of cohesion during storage, because the disintegration time will not increase too much even if it increases. This is equivalent to batch 3 in Example 1 using a different wax. The two examples show that if the unbound excess coating material is effectively removed by sieving, it is possible to minimize or prevent coating in pharmaceutical products during storage, specifically at higher temperatures and after extended storage periods. Cohesion of the covering material.

實例 3 ：用Sasol (合成)蠟以26:74之理論塗覆比塗覆伊布洛芬。塗覆後，隨後對經塗覆之伊布洛芬進行篩分。使用50:50之劑量比產生冷凍乾燥之錠劑且在三個月內進行測試。伊布洛芬強度為200 mg。如上文實例1及2中，在25℃/60% RH、30℃/65% RH及40℃/75% RH之ICH穩定性條件下測試每一批次。亦將樣品暴露於50℃應力條件以提供每一研究期間之兩週及四週時之加速數據。下表4提供50:50 Sasol蠟塗覆之伊布洛芬之三個月研究的數據。批次6之經篩分之塗覆之API的微鏡檢查(圖4F)顯示伊布洛芬經充分塗覆且具有一些未結合之塗覆材料。批次批號初始DT 2週 4週 1個月 1個月 1個月 2個月 2個月 2個月 3個月 3個月 3個月 50℃ 50℃ 25℃/60% 30℃/ 65% RH 40℃/ 75% RH 25℃/ 60% RH 30℃/ 65% RH 40℃/ 75% RH 25℃/ 60% RH 30℃/ 65% RH 40℃/ 75% RH 6 Z3876/142 ＜1 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 1 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s 7 Z3876/141/1 ＜2 s ＜5 s ＜5 s ＜2 s ＜3 s ＜3 s ＜ 2 s ＜ 2 s ＜ 3 s ＜ 2 s ＜ 2 s ＜ 3 s 表 4. Sasol 蠟 ( 計量比 50:50) 伊布洛芬強度： 200 mg Example 3 : Ibuprofen was coated with Sasol (synthetic) wax with a theoretical coating ratio of 26:74. After coating, the coated ibuprofen was then screened. A 50:50 dose ratio was used to produce freeze-dried lozenges and tested within three months. The strength of Ibuprofen is 200 mg. As in Examples 1 and 2 above, each batch was tested under the ICH stability conditions of 25°C/60% RH, 30°C/65% RH, and 40°C/75% RH. The samples were also exposed to 50°C stress conditions to provide acceleration data at two and four weeks in each study period. Table 4 below provides data from a three-month study of 50:50 Sasol wax-coated Ibuprofen. Microscopic examination of the sieved coated API of Batch 6 (Figure 4F) showed that ibuprofen was fully coated with some unbound coating material. batch batch number Initial DT Two weeks 4 weeks 1 month 1 month 1 month 2 months 2 months 2 months 3 months 3 months 3 months 50℃ 50℃ 25℃/60% 30℃/65% RH 40℃/ 75% RH 25℃/ 60% RH 30℃/65% RH 40℃/ 75% RH 25℃/ 60% RH 30℃/65% RH 40℃/ 75% RH 6 Z3876/142 ＜1 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 1 s ＜ 2 s ＜ 2 s ＜ 2 s ＜ 2 s 7 Z3876/141/1 ＜2 s ＜5 s ＜5 s ＜2 s ＜3 s ＜3 s ＜ 2 s ＜ 2 s ＜ 3 s ＜ 2 s ＜ 2 s ＜ 3 s Table 4. Sasol wax ( 50:50 metering ratio ) Ibuprofen strength: 200 mg

在三個月之研究過程中，批次6及批次7皆不顯示崩解時間顯著變化。具體地，批次6之樣品之初始崩解時間為約一秒，且三種ICH穩定性條件(25℃/60% RH、30℃/65% RH及40℃/75% RH)中每一者之最終三個月之崩解時間為約兩秒。批次6之兩週及四週加速50℃條件下之崩解時間均為約兩秒。During the three-month study, neither batch 6 nor batch 7 showed a significant change in disintegration time. Specifically, the initial disintegration time of batch 6 samples is about one second, and each of the three ICH stability conditions (25°C/60% RH, 30°C/65% RH, and 40°C/75% RH) The disintegration time in the final three months is about two seconds. The disintegration time of batch 6 under the condition of accelerated 50℃ for two weeks and four weeks was about two seconds.

批次7之樣品之初始崩解時間為約兩秒，且25℃/60% RH及30℃/65% RH ICH穩定性條件下之最後三個月崩解時間為約兩秒。40℃/75% RH ICH穩定性條件之最後三個月之崩解時間為約三秒。兩週及四週加速50℃條件下之崩解時間均為約五秒。50:50之高塗覆比可增加未篩分時過量未結合之塗覆材料之量。儘管兩個批次皆使用50:50之較高計量比，此意味著高負載之經塗覆之伊布洛芬及任何未結合之過量塗覆材料，但該等數據推斷經塗覆之伊布洛芬之篩分製程在去除未結合之過量塗覆材料以使黏聚最小化方面係有效的。The initial disintegration time of the batch 7 samples is about two seconds, and the disintegration time of the last three months under the stability conditions of 25°C/60% RH and 30°C/65% RH is about two seconds. The disintegration time in the last three months of 40℃/75% RH ICH stability conditions is about three seconds. The disintegration time under the conditions of accelerated 50℃ for two weeks and four weeks is about five seconds. The high coating ratio of 50:50 can increase the amount of excessive unbound coating material when not sieved. Although both batches use a higher dosing ratio of 50:50, which means a high load of coated ibuprofen and any unbound excess coating material, these data infer the coated ibuprofen The screening process of ibuprofen is effective in removing unbound excess coating materials to minimize cohesion.

實例 4 ：用巴西棕櫚蠟以22.5:77.5及30:70之理論塗覆比塗覆伊布洛芬。使用30:70之計量比製備冷凍乾燥之錠劑，且在2個月之時段內進行研究。伊布洛芬強度為200 mg。將批料儲存在40℃下之烘箱中。在最初、第25天及2個月時間點測試錠劑之崩解時間。下表5提供該研究之崩解時間。顯微鏡檢查未篩分之經塗覆之伊布洛芬(圖4G及4H)及經篩分之經塗覆之伊布洛芬(圖4I及4J)。伊布洛芬經充分塗覆。經篩分樣品不存在未結合之塗覆材料。批次批號經塗覆之API 塗覆比初始第24天於40℃下 2個月於40℃下 8 Z4750/186/2a 未篩分 22.5 : 77.5 5s 2s 2s 9 Z4750/186/4a 經篩分 22.5:77.5 4s 3s 3s 10 Z4750/186/6a 未篩分 30:70 1s 2s 2s 11 Z4750/186/8a 經篩分 30:70 2s 3s 3s 表 5. 巴西棕櫚蠟 ( 計量比 30:70) 伊布洛芬強度： 200 mg Example 4 : Ibuprofen was coated with carnauba wax at a theoretical coating ratio of 22.5:77.5 and 30:70. The freeze-dried lozenges were prepared using a 30:70 metering ratio, and the study was conducted over a period of 2 months. The strength of Ibuprofen is 200 mg. Store the batch in an oven at 40°C. The disintegration time of the tablets was tested at the first, 25th day and 2 month time points. Table 5 below provides the disintegration time for this study. The unsieved coated ibuprofen (Figures 4G and 4H) and the sieved coated ibuprofen (Figures 4I and 4J) were examined microscopically. Ibuprofen is fully coated. The sieved sample has no unbound coating material. batch batch number Coated API Coating ratio initial At 40°C on the 24th day 2 months at 40℃ 8 Z4750/186/2a Not sieved 22.5: 77.5 5s 2s 2s 9 Z4750/186/4a Sieved 22.5:77.5 4s 3s 3s 10 Z4750/186/6a Not sieved 30:70 1s 2s 2s 11 Z4750/186/8a Sieved 30:70 2s 3s 3s Table 5. Carnauba wax ( dosing ratio 30:70) Ibuprofen strength: 200 mg

批次8-11顯示，對於未篩分(批次8及10)或經篩分(批次9及11)之經塗覆之伊布洛芬，使用30:70之計量比，在40℃下儲存之錠劑之崩解時間未隨時間增加。此支持如下假說：藉由降低計量比，例如降低至30:70，過量未結合之蠟之量足夠降低至可使過量未結合之材料在較高溫度下儲存時隨時間之黏聚最小化的程度。Batches 8-11 show that for unsieved (batch 8 and 10) or sieved (batch 9 and 11) coated ibuprofen, a 30:70 metering ratio is used at 40°C The disintegration time of the lozenges stored below did not increase with time. This supports the hypothesis that by reducing the metering ratio, for example to 30:70, the amount of excess unbound wax is sufficiently reduced to minimize the cohesion of the excess unbound material over time when stored at higher temperatures degree.

上述實例之結果之總體概述於表6中製表。批次批號藥物強度(mg) 塗覆比計量比經塗覆API之篩分塗覆評價(顯微鏡檢查) 未結合之過量蠟(顯微鏡檢查) 於40℃/75%RH下1/ 2/ 3/ 6個月時之崩解時間於50℃下2/4wk時之崩解時間 1 Z3876/128 伊布洛芬 400 26:74 40:60 經篩分中等存在＜ 4 -7 s ＜ 4 - 10 s 2 Z4630/97 伊布洛芬 50 26:74 40:60 經篩分(差) 差存在＜ 2- 15 s ＜ 4 - 7 s 3 Z4630/101 伊布洛芬 50 26:74 40:60 經篩分 (充分) 良好不存在＜ 2 -3 s ＜ 3 - 4 s 4 Z3876/131 伊布洛芬 200 26:74 40:60 經篩分中等存在＜ 2 - 5 s ＜ 13 -20 s 5 Z3876/138 伊布洛芬 200 26:74 40:60 經篩分良好存在＜ 4 - 5s ＜ 3- 4 s 6 Z3876/142 伊布洛芬 200 26:74 50:50 經篩分良好存在＜ 2 s ＜ 2 s 7 Z3876/141/1 伊布洛芬 200 25:75 50:50 經篩分無照片無照片＜ 3 s ＜ 5 s 8 Z4750/186/2a 伊布洛芬 200 22.5: 77.5 30:70 未篩分良好存在＜ 2 s 無數據 9 Z4750/186/4a 伊布洛芬 200 22.5:77.5 30:70 經篩分 (充分) 良好不存在＜ 3 s 無數據 10 Z4750/186/6a 伊布洛芬 200 30:70 30:70 未篩分良好存在＜ 2 s 無數據 11 Z4750/186/8a 伊布洛芬 200 30:70 30:70 經篩分良好不存在＜ 3 s 無數據表 6. 批次 1-11 之結果之總體概述 . 保存功能性塗覆之伊布洛芬實例The overall summary of the results of the above examples is tabulated in Table 6. batch batch number drug Strength (mg) Coating ratio Measurement ratio Screening of coated API Coating evaluation (microscopic examination) Unbound excess wax (microscopic examination) Disintegration time at 1/2/3/6 months under 40℃/75%RH Disintegration time at 2/4wk at 50℃ 1 Z3876/128 Ibuprofen 400 26:74 40:60 Sieved medium exist ＜ 4 -7 s ＜ 4-10 s 2 Z4630/97 Ibuprofen 50 26:74 40:60 After screening (poor) difference exist ＜ 2- 15 s ＜ 4-7 s 3 Z4630/101 Ibuprofen 50 26:74 40:60 Sieved (full) good does not exist ＜ 2 -3 s ＜ 3-4 s 4 Z3876/131 Ibuprofen 200 26:74 40:60 Sieved medium exist ＜ 2-5 s ＜ 13 -20 s 5 Z3876/138 Ibuprofen 200 26:74 40:60 Sieved good exist ＜ 4-5s ＜ 3- 4 s 6 Z3876/142 Ibuprofen 200 26:74 50:50 Sieved good exist ＜ 2 s ＜ 2 s 7 Z3876/141/1 Ibuprofen 200 25:75 50:50 Sieved No photo No photo ＜ 3 s ＜ 5 s 8 Z4750/186/2a Ibuprofen 200 22.5: 77.5 30:70 Not sieved good exist ＜ 2 s no data 9 Z4750/186/4a Ibuprofen 200 22.5:77.5 30:70 Sieved (full) good does not exist ＜ 3 s no data 10 Z4750/186/6a Ibuprofen 200 30:70 30:70 Not sieved good exist ＜ 2 s no data 11 Z4750/186/8a Ibuprofen 200 30:70 30:70 Sieved good does not exist ＜ 3 s no data Table 6. General summary of results from batches 1-11 . Examples of preserved functionally coated Ibuprofen

實例 5 ：根據本文所述之實施例，使用疏水性發煙二氧化矽塗覆功能性塗覆之伊布洛芬。具體地，所使用之疏水性發煙二氧化矽係Aerosil R972 (「Aerosil」)。測試兩種不同濃度之Aerosil R972—1.5% w/w及1.0% w/w。在6小時之保持時段內評估功能性塗覆之伊布洛芬之大小，在保持時段期間使其經受低剪切混合。 Example 5 : According to the examples described herein, the functionally coated ibuprofen was coated with hydrophobic fuming silica. Specifically, the hydrophobic fuming silica used is Aerosil R972 ("Aerosil"). Test two different concentrations of Aerosil R972—1.5% w/w and 1.0% w/w. The size of the functionally coated ibuprofen was evaluated during the 6-hour holding period and subjected to low shear mixing during the holding period.

圖5、6及7分別提供在6小時時段內d10粒度、d50粒度及d90粒度之評估。一般而言，以其d10表示之粒度意指在給定量之樣品中10%之顆粒低於給定粒度。因此，以其d50表示之粒度意指在給定量之樣品中50%之顆粒低於給定粒度，且以其d90表示之粒度意指在給定量之樣品中90%之顆粒低於給定粒度。Figures 5, 6 and 7 provide the evaluation of the d10 particle size, d50 particle size and d90 particle size in a 6-hour period, respectively. Generally speaking, the particle size expressed by its d10 means that 10% of the particles in a given amount of sample are below the given particle size. Therefore, the particle size expressed by its d50 means that 50% of the particles in a given amount of sample are below the given size, and the particle size expressed by its d90 means that 90% of the particles in a given amount of sample are below the given size .

如圖5中所示，更大濃度之二氧化矽(1.5% w/w)比更低濃度之二氧化矽(1.0% w/w)更有效地維持初始粒度，且因此維持塗層。具體地，在6小時時段期間，包含1.5% w/w Aerosil之功能性塗覆之伊布洛芬損失其初始大小之約30%，而包含1.0% w/w Aerosil之功能性塗覆之伊布洛芬損失其初始粒度之約80%。As shown in Figure 5, a higher concentration of silica (1.5% w/w) maintains the initial particle size more effectively than a lower concentration of silica (1.0% w/w), and therefore the coating. Specifically, during a 6-hour period, the functionally coated ibuprofen containing 1.5% w/w Aerosil lost about 30% of its initial size, while the functionally coated ibuprofen containing 1.0% w/w Aerosil Ibuprofen loses approximately 80% of its initial particle size.

圖6展現，再次，更大濃度之二氧化矽(1.5% w/w Aerosil)比更低濃度之二氧化矽(1.0% w/w Aerosil)更有效地維持初始功能性塗覆之伊布洛芬粒度，且因此保存功能性塗層。具體地，在6小時時段期間，包含1.5 % w/w Aerosil之功能性塗覆之伊布洛芬損失其初始大小之幾乎20%，而包含1.0% w/w Aerosil之功能性塗覆之伊布洛芬損失其初始功能性塗覆之API粒度之約45%。Figure 6 shows that again, a higher concentration of silica (1.5% w/w Aerosil) is more effective in maintaining the initial functional coating of Iblood than a lower concentration of silica (1.0% w/w Aerosil) Fern particle size, and therefore preserve the functional coating. Specifically, during a 6-hour period, the functionally coated ibuprofen containing 1.5% w/w Aerosil lost almost 20% of its initial size, while the functionally coated ibuprofen containing 1.0% w/w Aerosil lost almost 20% of its initial size. Ibuprofen loses about 45% of the API particle size of its initial functional coating.

圖7亦顯示，更大濃度之二氧化矽(1.5% w/w Aerosil)比更低濃度之二氧化矽(1.0% w/w Aerosil)更有效地維持初始功能性塗覆之伊布洛芬粒度，且因此保存功能性塗覆之伊布洛芬的功能性塗層。具體地，在6小時時段期間，包含1.5 % w/w Aerosil之功能性塗覆之伊布洛芬損失其初始大小之幾乎15%，而包含1.0% w/w Aerosil之功能性塗覆之伊布洛芬損失其初始粒度之約35%。Figure 7 also shows that a higher concentration of silica (1.5% w/w Aerosil) is more effective in maintaining the initial functional coating of Ibuprofen than a lower concentration of silica (1.0% w/w Aerosil) Particle size, and thus preserve the functional coating of functionally coated ibuprofen. Specifically, during the 6-hour period, the functionally coated ibuprofen containing 1.5% w/w Aerosil lost almost 15% of its initial size, while the functional coated ibuprofen containing 1.0% w/w Aerosil lost almost 15% of its initial size. Ibuprofen loses approximately 35% of its initial particle size.

此外，隨著功能性塗覆之伊布洛芬之粒度減小，出現包含5 μm至20 μm之粒度之單獨顆粒群體，且隨時間增加。據信該等顆粒係在塗層由於剪切力而侵蝕之前包埋於變形之連續塗覆材料中的不可變形之塗覆材料顆粒。因此，隨著塗層侵蝕，且功能性塗覆之伊布洛芬之粒度減小，該等較小顆粒之群體大小隨著包圍其之變形塗覆材料侵蝕而增加，從而導致該等不可變形顆粒自功能性塗覆之伊布洛芬釋放。In addition, as the particle size of the functionally coated ibprofen decreases, a single particle population containing a particle size of 5 μm to 20 μm appears and increases with time. It is believed that the particles are non-deformable coating material particles that are embedded in the deformed continuous coating material before the coating erodes due to shear forces. Therefore, as the coating erodes and the particle size of the functionally coated ibprofen decreases, the population size of these smaller particles increases as the deformed coating material surrounding it erodes, resulting in the non-deformable The particles are released from the functionally coated ibuprofen.

總之，該等試驗表明，塗覆功能性塗覆之伊布洛芬之1.5% w/w Aerosil可將「處理窗」增加至約4小時，而非在無二氧化矽之情況下存在之2小時「處理窗」。在懸浮液中處理且包含含有1.5% w/w Aerosil之第二外塗層之前四小時內，功能性塗覆之伊布洛芬展現極少塗層侵蝕，若有的話。In summary, these tests show that the functional coating of 1.5% w/w Aerosil of Ibuprofen can increase the "treatment window" to about 4 hours, rather than the presence of silicon dioxide in the absence of 2 Hour "processing window". Within four hours before being processed in suspension and containing a second outer coating containing 1.5% w/w Aerosil, the functionally coated ibuprofen exhibited very little coating erosion, if any.

實例 6 ：根據本文所述之實施例，使用疏水性發煙二氧化矽塗覆功能性塗覆之伊布洛芬。具體地，所使用之疏水性發煙二氧化矽係Aerosil R972 (「Aerosil」)。測試五種不同濃度之Aerosil R972—0.0 % w/w、1.5% w/w、2.5% w/w、5.0% w/w及10.0% w/w。使用溶解測試(即0.01% SDS於pH 7.2磷酸鹽緩衝液中之溶解介質，介質溫度為37℃，且介質體積為10ml(伊布洛芬))評估功能性塗覆之伊布洛芬之釋放量。 Example 6 : According to the examples described herein, the functionally coated ibuprofen was coated with hydrophobic fuming silica. Specifically, the hydrophobic fuming silica used is Aerosil R972 ("Aerosil"). Test five different concentrations of Aerosil R972—0.0% w/w, 1.5% w/w, 2.5% w/w, 5.0% w/w and 10.0% w/w. Use dissolution test (ie 0.01% SDS in pH 7.2 phosphate buffer solution medium, medium temperature is 37℃, and medium volume is 10ml (ibuprofen)) to evaluate the release of functionally coated ibuprofen the amount.

圖8及9提供在5或30分鐘之時段內對功能性塗覆之伊布洛芬執行之釋放量之評估。一般而言，以其釋放%表示之低體積溶解結果意指之「x」重量%之所添加之材料已溶解至溶液中。Figures 8 and 9 provide an assessment of the release of functionally coated ibuprofen over a period of 5 or 30 minutes. Generally speaking, the low-volume dissolution result expressed in% release means that "x" wt% of the added material has been dissolved into the solution.

圖8顯示用巴西棕櫚蠟及各種量之疏水性二氧化矽塗覆之伊布洛芬的釋放數據。如圖中所示，更大濃度之二氧化矽(高達10.0% w/w)比更低濃度之二氧化矽更有效地在溶解測試中提供較慢之釋放速率，且因此維持塗層。具體地，在5分鐘測試時段期間，包含10.0% w/w Aerosil之功能性塗覆之伊布洛芬(即，用巴西棕櫚蠟塗覆之伊布洛芬)在5分鐘後展現1.5%釋放，而包含0.0% w/w Aerosil之功能性塗覆之伊布洛芬展現24.9%釋放。包含中等含量之Aerosil (即1.5% w/w、2.5% w/w及5.0% w/w)之功能性塗覆之伊布洛芬在5分鐘後分別顯示12.1%釋放、7.4%釋放及2.3%釋放之溶解結果。Figure 8 shows the release data of ibuprofen coated with carnauba wax and various amounts of hydrophobic silica. As shown in the figure, higher concentrations of silica (up to 10.0% w/w) are more effective in providing a slower release rate in the dissolution test than lower concentrations of silica, and therefore maintain the coating. Specifically, during the 5-minute test period, functionally coated Ibuprofen containing 10.0% w/w Aerosil (ie, Ibuprofen coated with carnauba wax) exhibited a release of 1.5% after 5 minutes , And functionally coated Ibuprofen containing 0.0% w/w Aerosil showed a 24.9% release. Functionally coated Ibuprofen containing a moderate amount of Aerosil (i.e. 1.5% w/w, 2.5% w/w and 5.0% w/w) showed 12.1% release, 7.4% release and 2.3% after 5 minutes. % Dissolution result of release.

圖9提供用Sasol (合成)蠟及各種含量之疏水性二氧化矽塗覆之伊布洛芬的釋放數據。圖10亦顯示，更大濃度之二氧化矽(高達10.0% w/w)比更低濃度之二氧化矽更有效地在溶解測試中提供較慢之釋放速率，且因此維持塗層。具體地，在5分鐘測試時段期間，包含10.0% w/w Aerosil之功能性塗覆之伊布洛芬(即，用合成蠟塗覆之伊布洛芬)在5分鐘後展現2.8 %釋放，而包含0.0% w/w Aerosil之功能性塗覆之伊布洛芬顯示8.5 %釋放。包含中等含量之Aerosil (即1.5% w/w、2.5% w/w及5.0% w/w)之功能性塗覆之伊布洛芬在5分鐘後分別產生4.3 %釋放、3.6 %釋放及2.4 %釋放之溶解結果。最小化通氣實例Figure 9 provides release data of ibuprofen coated with Sasol (synthetic) wax and various levels of hydrophobic silica. Figure 10 also shows that higher concentrations of silica (up to 10.0% w/w) are more effective in providing a slower release rate in the dissolution test than lower concentrations of silica, and therefore maintain the coating. Specifically, during the 5-minute test period, functionally coated Ibuprofen containing 10.0% w/w Aerosil (ie, Ibuprofen coated with synthetic wax) exhibited a 2.8% release after 5 minutes, The functionally coated Ibuprofen containing 0.0% w/w Aerosil showed a release of 8.5%. Functionally coated ibuprofen containing a moderate amount of Aerosil (i.e. 1.5% w/w, 2.5% w/w and 5.0% w/w) produced 4.3% release, 3.6% release and 2.4% release after 5 minutes. % Dissolution result of release. Minimal ventilation example

包含萜烯及/或萜品醇之化學化合物在使通氣最小化方面之有效性可部分地藉由量測醫藥懸浮液中疏水性經塗覆之伊布洛芬隨時間之粒度來確定。若化學化合物係有效的，則懸浮液之通氣性將足夠低，且疏水性經塗覆之伊布洛芬之粒度將隨時間保持恆定或減小極小。若無效，則懸浮液之通氣量將高於期望之通氣量，且疏水性經塗覆之伊布洛芬之粒度可隨時間更顯著地減小。藉由量測混合容器中泡沫之高度來評價懸浮液之通氣程度。功能性塗覆之顆粒之粒度可使用雷射繞射、顆粒分析儀(例如Malvern Mastersizer)或分析細顆粒之任何其他適宜構件來量測。The effectiveness of chemical compounds containing terpenes and/or terpineol in minimizing ventilation can be determined in part by measuring the particle size of hydrophobic coated ibuprofen over time in pharmaceutical suspensions. If the chemical compound is effective, the air permeability of the suspension will be sufficiently low, and the particle size of the hydrophobic coated ibuprofen will remain constant or decrease extremely over time. If it is ineffective, the aeration of the suspension will be higher than the desired aeration, and the particle size of the hydrophobic coated ibuprofen can be reduced more significantly over time. The degree of ventilation of the suspension is evaluated by measuring the height of the foam in the mixing container. The particle size of the functionally coated particles can be measured using laser diffraction, a particle analyzer (such as Malvern Mastersizer), or any other suitable means for analyzing fine particles.

實例 7 ：藉由將經塗覆之伊布洛芬混合於含有不同含量檸檬烯、橙味矯味劑及草莓味矯味劑之基質溶液/懸浮液中，製造一系列懸浮液混合物。來自該等懸浮液之泡沫之高度分別概述於表7、8及9中。檸檬烯之濃度(% w/w) 泡沫高度(mm) 0 5 0.15 2 0.30 1 0.6 1 表 7 ： 來自含有不同含量之檸檬烯之混合物之泡沫的高度 . 橙味矯味劑之濃度(% w/w) 泡沫高度(mm) 0 5 0.15 1 0.30 0 0.6 0 表 8 ：來自含有不同含量之 橙味矯味劑 之混合物之泡沫的高度 . 草莓味矯味劑之濃度(% w/w) 泡沫高度(mm) 0 5 0.15 3 0.30 3 0.6 3 表 9 ：來自含有不同含量之草莓 味 矯味劑之混合物之泡沫的高度 . Example 7 : A series of suspension mixtures were prepared by mixing the coated ibuprofen in a matrix solution/suspension containing different contents of limonene, orange flavor and strawberry flavor. The height of the foam from these suspensions is summarized in Tables 7, 8 and 9, respectively. Limonene concentration (% w/w) Foam height (mm) 0 5 0.15 2 0.30 1 0.6 1 Table 7 : Height of foam from mixtures containing different levels of limonene . Concentration of orange flavor (% w/w) Foam height (mm) 0 5 0.15 1 0.30 0 0.6 0 Table 8 : The height of foam from mixtures containing different orange flavoring agents . Concentration of strawberry flavor corrective (% w/w) Foam height (mm) 0 5 0.15 3 0.30 3 0.6 3 Table 9: Foam height from a mixture containing strawberry flavor taste different amounts of correction of the.

表7及8中之結果顯示，以0.15% w/w及以上之含量添加檸檬烯及橙味矯味劑使通氣最小化。對於草莓(表9)，其亦減少通氣，但未減少至相同程度。The results in Tables 7 and 8 show that the addition of limonene and orange flavoring agents at 0.15% w/w and above minimizes ventilation. For strawberries (Table 9), it also reduced aeration, but not to the same extent.

實例 8 ：圖10、11及12顯示包含各種濃度之液體橙味矯味劑之醫藥懸浮液中疏水性經塗覆之伊布洛芬之粒度(分別為d10、d50及d90)減小。以其d10表示之粒度意指在給定體積之樣品中10%之顆粒低於給定粒度。因此，d50粒度表示在給定體積之樣品中50%之顆粒低於給定粒度，且d90粒度表示在給定體積之樣品中90%之顆粒低於給定粒度。具體地，圖10-12顯示含有疏水性經塗覆之伊布洛芬及液體橙味矯味劑之懸浮液調配物的測試結果，該液體橙味矯味劑之濃度包括0.0%、0.15%、0.45%及0.60% w/w，在低剪切混合下保持高達6小時之時段。 Example 8 : Figures 10, 11 and 12 show that the particle size (d10, d50, and d90, respectively) of the hydrophobic coated ibprofen in pharmaceutical suspensions containing various concentrations of liquid orange flavoring agent is reduced. The particle size expressed by its d10 means that 10% of the particles in a given volume of sample are below the given particle size. Therefore, d50 particle size means that 50% of the particles in a given volume of sample are below the given particle size, and d90 particle size means that 90% of the particles in a given volume of sample are below the given particle size. Specifically, Figures 10-12 show the test results of a suspension formulation containing hydrophobic coated Ibuprofen and a liquid orange flavoring agent. The concentration of the liquid orange flavoring agent includes 0.0%, 0.15%, 0.45 % And 0.60% w/w, maintained for up to 6 hours under low shear mixing.

在高達0.45% w/w之橙味矯味劑之濃度(包括0.15% w/w)下，前2小時「處理窗」內d10、d50及d90粒度之減小很大程度上類似於包含疏水性經塗覆之伊布洛芬而無任何液體矯味劑(0%液體矯味劑)之醫藥懸浮液的減小。然而，在0.6% w/w液體橙味矯味劑之濃度下，容易去除疏水性經塗覆之伊布洛芬之塗層，且觀察到粒度快速減小。此外，在0.3% w/w之液體橙味矯味劑濃度下，懸浮液之通氣足夠低，對經塗覆之伊布洛芬之塗層之損害極小(若有的話)，且疏水性經塗覆之伊布洛芬之粒度僅有最小之減小。At the concentration of orange flavor up to 0.45% w/w (including 0.15% w/w), the particle size reduction of d10, d50 and d90 within the first 2 hours "treatment window" is largely similar to the inclusion of hydrophobicity Reduction of medicinal suspension of coated ibuprofen without any liquid flavoring agent (0% liquid flavoring agent). However, at a concentration of 0.6% w/w liquid orange flavoring agent, it is easy to remove the hydrophobic coating of Ibuprofen, and a rapid decrease in particle size is observed. In addition, at a concentration of 0.3% w/w of the liquid orange flavoring agent, the ventilation of the suspension is sufficiently low, the damage to the coating of the coated ibuprofen is minimal (if any), and the hydrophobicity is The particle size of the coated ibuprofen has only minimal reduction.

實例 9 ：圖13、14及15分別提供對於特定組分檸檬烯(其發現於一些液體矯味劑中)疏水性經塗覆之伊布洛芬之d10、d50及d90粒度減小的數據。執行該等測試以探索液體矯味劑之特定組分檸檬烯對懸浮液中之疏水性經塗覆之伊布洛芬的行為。注意，圖中所示之檸檬烯之濃度顯著大於若使用液體矯味劑時存在之檸檬烯的濃度。在圖13-15中，純檸檬烯以0.25% w/w、0.50% w/w及0.75% w/w之濃度使用，且在24小時之時段內進行測試。如所有三個圖中所示，與0.50% w/w及0.75% w/w之檸檬烯濃度相比，0.25% w/w之檸檬烯濃度對疏水性經塗覆之伊布洛芬之粒度的有害影響小得多。此外，所測試具有0.25% w/w檸檬烯之醫藥懸浮液包含足夠低之通氣量。因此，該等測試確認圖13-15中測試之液體橙味矯味劑之檸檬烯至少部分地負責醫藥懸浮液之通氣最小化，且隨後以相對高之量及/或在相對高之暴露時間侵蝕疏水性經塗覆之伊布洛芬之塗層。 Example 9 : Figures 13, 14 and 15 respectively provide data on the particle size reduction of d10, d50 and d90 of hydrophobic coated ibprofen for a specific component of limonene (which is found in some liquid flavoring agents). These tests were performed to explore the behavior of limonene, a specific component of the liquid flavoring agent, on the hydrophobic coated ibuprofen in suspension. Note that the concentration of limonene shown in the figure is significantly greater than the concentration of limonene present if a liquid flavoring agent is used. In Figures 13-15, pure limonene was used in concentrations of 0.25% w/w, 0.50% w/w and 0.75% w/w, and tested within a 24-hour period. As shown in all three figures, the limonene concentration of 0.25% w/w is harmful to the particle size of the hydrophobic coated ibprofen compared to the limonene concentration of 0.50% w/w and 0.75% w/w The impact is much smaller. In addition, the tested pharmaceutical suspensions with 0.25% w/w limonene contained sufficiently low ventilation. Therefore, these tests confirm that the limonene of the liquid orange flavoring agent tested in Figures 13-15 is at least partly responsible for minimizing the aeration of the pharmaceutical suspension, and subsequently corrodes the hydrophobicity in relatively high amounts and/or at relatively high exposure times. Sexually coated Ibuprofen coating.

實例 10 ：圖16顯示兩種不同液體矯味劑-草莓及橙之測試數據。針對草莓液體矯味劑及橙液體矯味劑二者測試疏水性經塗覆之伊布洛芬之d10、d50及d90粒度。草莓味及橙味液體矯味劑二者皆包含檸檬烯。如圖中所示，兩種矯味劑關於疏水性經塗覆之伊布洛芬粒度之表現類似。d10顆粒樣品在試驗之前兩小時內顯示比d50及d90粒度樣品更大量之粒度減小。d50及d90粒度樣品在相同兩小時時段內展現較少之粒度減小。然而，此觀察結果與先前論述之實例之d10、d50及d90粒度之數據一致。 Example 10 : Figure 16 shows the test data of two different liquid flavoring agents-strawberry and orange. The d10, d50, and d90 particle sizes of the hydrophobic coated Ibuprofen were tested for both strawberry liquid flavoring agent and orange liquid flavoring agent. Both the strawberry flavor and orange flavor liquid flavoring agents contain limonene. As shown in the figure, the two flavors performed similarly with respect to the particle size of the hydrophobic coated ibuprofen. The d10 particle sample showed a greater particle size reduction than the d50 and d90 particle size samples within two hours before the test. The d50 and d90 particle size samples exhibited less particle size reduction within the same two-hour period. However, this observation is consistent with the d10, d50, and d90 granularity data of the previously discussed examples.

另外，觀察到在所有試驗中，隨著疏水性塗覆之API (伊布洛芬)顆粒之粒度減小，出現包含5 μm至20 μm之粒度之單獨顆粒群體，且其隨著時間而增加。據信該等顆粒係在塗層由於剪切力而侵蝕之前包埋於變形之連續塗覆材料中的不可變形之塗覆材料顆粒。因此，隨著塗層侵蝕，且疏水性塗覆之伊布洛芬之粒度減小，該等較小顆粒之群體大小隨著包圍其之變形塗覆材料侵蝕而增加，從而導致該等不可變形顆粒自疏水性塗覆之伊布洛芬釋放。In addition, it was observed that in all experiments, as the particle size of the hydrophobic coated API (Ibuprofen) particles decreased, a separate particle population containing a particle size of 5 μm to 20 μm appeared, and it increased with time . It is believed that the particles are non-deformable coating material particles that are embedded in the deformed continuous coating material before the coating erodes due to shear forces. Therefore, as the coating erodes and the particle size of the hydrophobic coated ibprofen decreases, the population size of the smaller particles increases as the deformed coating material surrounding it erodes, resulting in the non-deformable The particles are released from the hydrophobically coated Ibuprofen.

總之，該等試驗顯示，藉由最佳化添加至包含疏水性經塗覆之伊布洛芬之醫藥懸浮液中之萜烯檸檬烯的量，可使懸浮液中之通氣量最小化以允許下游處理，而同時對疏水性經塗覆之伊布洛芬之塗層沒有不良效應(藉由疏水性經塗覆之伊布洛芬之粒度來確定)。In summary, these experiments have shown that by optimizing the amount of terpene limonene added to a pharmaceutical suspension containing hydrophobic coated ibuprofen, the aeration in the suspension can be minimized to allow downstream Treatment without adverse effects on the coating of hydrophobic coated Ibuprofen (determined by the particle size of hydrophobic coated Ibuprofen).

出於解釋之目的，已參考具體實施例闡述了前述說明。然而，以上說明性論述並不意欲為窮盡性的或將本發明限制於所揭示之精確形式。鑒於以上教示，許多修改及變化係可能的。選擇及闡述實施例以最佳地解釋技術之原理及其實際應用。因此，業內之其他技術人員能夠最佳地利用具有適於所考慮之特定用途之各種修改的技術及各種實施例。For the purpose of explanation, the foregoing description has been explained with reference to specific embodiments. However, the illustrative discussion above is not intended to be exhaustive or to limit the invention to the precise form disclosed. In view of the above teachings, many modifications and changes are possible. The embodiments are selected and described to best explain the principle of the technology and its practical application. Therefore, other technicians in the industry can make best use of the technology and various embodiments with various modifications suitable for the specific use under consideration.

儘管已參考附圖充分闡述本揭示內容及實例，但應注意，各種改變及修改對於熟習此項技術者將變得顯而易見。該等改變及修改應理解為包括在由申請專利範圍界定之本揭示內容及實例的範疇內。Although the present disclosure and examples have been fully explained with reference to the drawings, it should be noted that various changes and modifications will become obvious to those familiar with the art. Such changes and modifications should be understood to be included in the scope of this disclosure and examples defined by the scope of the patent application.

102:API顆粒 104:塗覆材料顆粒/連續變形之膜層/連續膜/塗層 108:固體不可變形顆粒 312:經塗覆之API顆粒 314:「鬆散的」或「游離的」塗覆材料顆粒102: API particles 104: Coating material particles/continuously deformed film/continuous film/coating 108: solid non-deformable particles 312: Coated API particles 314: "Loose" or "free" coating material particles

現將參照附圖僅以舉例說明方式闡述本發明，其中：The present invention will now be explained by way of example only with reference to the drawings, in which:

圖1A顯示根據一些實施例經可變形塗覆材料之顆粒(即，第一塗覆層)塗覆的API顆粒；Figure 1A shows API particles coated with particles of a deformable coating material (ie, the first coating layer) according to some embodiments;

圖1B顯示根據一些實施例經可變形塗覆材料之連續膜層(即，第一塗覆層)塗覆的API顆粒；Figure 1B shows API particles coated with a continuous film layer (ie, the first coating layer) of a deformable coating material according to some embodiments;

圖1C顯示根據一些實施例之經可變形塗覆材料之連續膜層(即，第一塗覆層)塗覆的API顆粒，其中二氧化矽之顆粒(即，第二塗覆層)部分包埋及/或包埋於第一塗覆層之表面上；Figure 1C shows API particles coated with a continuous film layer of a deformable coating material (ie, the first coating layer) according to some embodiments, wherein the particles of silicon dioxide (ie, the second coating layer) partially cover Buried and/or embedded on the surface of the first coating layer;

圖2顯示根據一些實施例之未經塗覆之API顆粒之掃描電子顯微鏡(SEM)影像；Figure 2 shows scanning electron microscope (SEM) images of uncoated API particles according to some embodiments;

圖3顯示根據一些實施例之經塗覆之API顆粒之SEM影像；Figure 3 shows SEM images of coated API particles according to some embodiments;

圖4A-4J係由實例1-4之經篩分塗覆之伊布洛芬獲取之一系列顯微照片；Figures 4A-4J are a series of photomicrographs obtained from the sieved-coated Ibuprofen of Examples 1-4;

圖5係根據一些實施例之提供對包含不同濃度之二氧化矽之第二保護性塗層的功能性塗覆之伊布洛芬之d10粒度之評價的圖；FIG. 5 is a diagram that provides an evaluation of the d10 particle size of functionally coated Ibuprofen including a second protective coating of silica at different concentrations according to some embodiments;

圖6顯示根據一些實施例之提供對包含不同濃度之二氧化矽之第二保護性塗層的功能性塗覆之伊布洛芬之d50粒度之評價的圖；FIG. 6 shows a graph that provides an evaluation of the d50 particle size of functionally coated Ibuprofen including a second protective coating of silica at different concentrations according to some embodiments;

圖7顯示根據一些實施例之提供對包含不同濃度之二氧化矽之第二保護性塗層的功能性塗覆之伊布洛芬之d90粒度之評價的圖；FIG. 7 shows a graph that provides an evaluation of the d90 particle size of functionally coated Ibuprofen including a second protective coating of silica at different concentrations according to some embodiments;

圖8顯示經具有不同含量之疏水性發煙二氧化矽之巴西棕櫚蠟塗覆的伊布洛芬之低體積溶解的圖；Figure 8 shows the low volume dissolution of ibuprofen coated with carnauba wax with different content of hydrophobic fuming silica;

圖9顯示經包含不同含量之疏水性發煙二氧化矽之Sasol (合成)蠟塗覆的伊布洛芬之低體積溶解的圖；Figure 9 shows a graph of low volume dissolution of Ibuprofen coated with Sasol (synthetic) wax containing different levels of hydrophobic fuming silica;

圖10顯示提供對具有不同濃度之液體矯味劑之疏水性經塗覆之伊布洛芬之d10粒度之評估的圖；Figure 10 shows a graph that provides an assessment of the d10 particle size of hydrophobic coated Ibuprofen with different concentrations of liquid flavoring agents;

圖11顯示提供對具有不同濃度之液體矯味劑之疏水性經塗覆之伊布洛芬之d50粒度之評估的圖；Figure 11 shows a graph that provides an evaluation of the d50 particle size of hydrophobic coated Ibuprofen with different concentrations of liquid flavoring agents;

圖12顯示提供對具有不同濃度之液體矯味劑之疏水性經塗覆之伊布洛芬之d90粒度之評估的圖；Figure 12 shows a graph providing the evaluation of the d90 particle size of hydrophobic coated Ibuprofen with different concentrations of liquid flavoring agents;

圖13顯示提供對具有不同濃度之純檸檬烯之疏水性經塗覆之伊布洛芬之d10粒度之評估的圖；Figure 13 shows a graph providing the evaluation of the d10 particle size of hydrophobic coated Ibuprofen with different concentrations of pure limonene;

圖14顯示提供對具有不同濃度之純檸檬烯之疏水性經塗覆之伊布洛芬之d50粒度之評估的圖；Figure 14 shows a graph that provides an assessment of the d50 particle size of hydrophobic coated Ibuprofen with different concentrations of pure limonene;

圖15顯示提供對具有不同濃度之純檸檬烯之疏水性經塗覆之伊布洛芬之d90粒度之評估的圖；且Figure 15 shows a graph that provides an assessment of the d90 particle size of hydrophobic coated Ibuprofen with different concentrations of pure limonene; and

圖16顯示比較疏水性經塗覆之伊布洛芬與草莓味及橙子味液體矯味劑之各種粒度分析的圖。Figure 16 shows a graph comparing various particle size analysis of hydrophobic coated Ibuprofen and strawberry flavor and orange flavor liquid correctives.

102:API顆粒 102: API particles

104:塗覆材料顆粒/連續變形之膜層/連續膜/塗層 104: Coating material particles/continuously deformed film/continuous film/coating

108:固體不可變形顆粒 108: solid non-deformable particles

Claims

一種醫藥組合物，其包含： 65-85 % w/w伊布洛芬(Ibuprofen)； 15-30 % w/w塗覆該伊布洛芬之塗覆材料；及 3-15 % w/w包圍該伊布洛芬之基質。A pharmaceutical composition comprising: 65-85% w/w Ibuprofen (Ibuprofen); 15-30% w/w coating material of Ibuprofen; and 3-15% w/w surrounds the matrix of Ibuprofen.

如請求項1之醫藥組合物，其包含50-400 mg伊布洛芬。The pharmaceutical composition of claim 1, which contains 50-400 mg of ibuprofen.

如請求項1之醫藥組合物，其中該塗覆材料包含第一塗覆材料及第二塗覆材料，且該醫藥組合物包含10-30 % w/w該第一塗覆材料及0.5-10 % w/w該第二塗覆材料。The pharmaceutical composition of claim 1, wherein the coating material comprises a first coating material and a second coating material, and the pharmaceutical composition comprises 10-30% w/w of the first coating material and 0.5-10 % w/w of the second coating material.

如請求項3之醫藥組合物，其中該第一塗覆材料包含蠟。The pharmaceutical composition of claim 3, wherein the first coating material comprises wax.

如請求項4之醫藥組合物，其中該第二塗覆材料包含二氧化矽。The pharmaceutical composition of claim 4, wherein the second coating material comprises silicon dioxide.

如請求項1之醫藥組合物，其包含1-5% w/w防通氣劑。The pharmaceutical composition of claim 1, which contains 1-5% w/w anti-ventilation agent.

如請求項4之醫藥組合物，其中該第一塗覆材料包含巴西棕櫚蠟、合成蠟或小燭樹蠟中之一或多者。The pharmaceutical composition of claim 4, wherein the first coating material comprises one or more of carnauba wax, synthetic wax, or candelilla wax.

如請求項1之醫藥組合物，其中該基質包含基質形成劑及結構形成劑。The pharmaceutical composition of claim 1, wherein the matrix comprises a matrix forming agent and a structure forming agent.

如請求項8之醫藥組合物，其中該基質形成劑包含水溶性材料、水可分散材料、多肽、多醣、聚乙烯醇、聚乙烯基吡咯啶酮及***樹膠中之一或多者。The pharmaceutical composition of claim 8, wherein the matrix forming agent comprises one or more of water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone and gum arabic.

如請求項8之醫藥組合物，其中該基質形成劑包含多肽。The pharmaceutical composition of claim 8, wherein the matrix forming agent comprises a polypeptide.

如請求項10之醫藥組合物，其中該多肽包含明膠。The pharmaceutical composition of claim 10, wherein the polypeptide comprises gelatin.

如請求項8之醫藥組合物，其中該結構形成劑包含甘露醇、右旋糖、乳糖、半乳糖及環糊精中之一或多者。The pharmaceutical composition of claim 8, wherein the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

如請求項8之醫藥組合物，其中該結構形成劑包含甘露醇。The pharmaceutical composition of claim 8, wherein the structure forming agent comprises mannitol.

如請求項1之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有3秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項1之醫藥組合物，其中該醫藥組合物在5分鐘後具有10%或更少之溶解測試結果。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dissolution test result of 10% or less after 5 minutes.

如請求項1之醫藥組合物，其中該醫藥組合物在5分鐘後具有5%或更少之溶解測試結果。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dissolution test result of 5% or less after 5 minutes.

如請求項1之醫藥組合物，其中該醫藥組合物在5分鐘後具有3%或更少之溶解測試結果。The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dissolution test result of 3% or less after 5 minutes.

如請求項1之醫藥組合物，其中該基質包含黏度調節劑。The pharmaceutical composition of claim 1, wherein the matrix contains a viscosity modifier.

如請求項30之醫藥組合物，其中該黏度調節劑包含黃原膠。The pharmaceutical composition of claim 30, wherein the viscosity modifier comprises xanthan gum.

如請求項6之醫藥組合物，其中該防通氣劑包含萜烯或萜品醇中之一或多者。The pharmaceutical composition of claim 6, wherein the anti-ventilation agent comprises one or more of terpene or terpineol.

如請求項6之醫藥組合物，其中該防通氣劑包含液體矯味劑。The pharmaceutical composition of claim 6, wherein the anti-ventilation agent comprises a liquid flavoring agent.

如請求項6之醫藥組合物，其中該防通氣劑包含含有檸檬烯之液體矯味劑。The pharmaceutical composition of claim 6, wherein the anti-ventilation agent comprises a liquid flavoring agent containing limonene.

如請求項6之醫藥組合物，其中該防通氣劑包含橙味矯味劑、檸檬味矯味劑、葡萄柚味矯味劑、酸檸檬味矯味劑、草莓味矯味劑或薄荷味矯味劑中之一或多者。The pharmaceutical composition of claim 6, wherein the anti-ventilation agent comprises one of an orange flavor corrective agent, a lemon flavor corrective agent, a grapefruit flavor corrective agent, a lime flavor corrective agent, a strawberry flavor corrective agent or a mint flavor corrective agent or More.

如請求項8之醫藥組合物，其中該醫藥組合物包含3-10% w/w基質形成劑。The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 3-10% w/w matrix forming agent.

如請求項8之醫藥組合物，其中該醫藥組合物包含3-10 % w/w結構形成劑。The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 3-10% w/w structure forming agent.

一種醫藥組合物，其係藉由包含以下步驟之方法製備：用第一塗覆材料塗覆伊布洛芬以形成經塗覆之伊布洛芬，其中該第一塗覆材料包含一或多種可變形組分；對該經塗覆之伊布洛芬施加機械應力以使該一或多種可變形組分變形；用包含二氧化矽之第二塗覆材料塗覆該經塗覆之伊布洛芬；施加機械應力以將該第二塗覆材料包埋至該經塗覆之伊布洛芬之該第一塗覆材料上；篩分該經塗覆之伊布洛芬以去除過量第一塗覆材料，其中該過量第一塗覆材料包含未結合至該經塗覆之伊布洛芬之第一塗覆材料；形成包含兩次塗覆之伊布洛芬及基質溶液或懸浮液的醫藥懸浮液；及將該醫藥懸浮液計量至模具中；及冷凍乾燥該模具中之該經計量之醫藥懸浮液以形成醫藥組合物。A pharmaceutical composition prepared by a method comprising the following steps: Coating ibuprofen with a first coating material to form a coated ibuprofen, wherein the first coating material includes one or more deformable components; Applying mechanical stress to the coated ibuprofen to deform the one or more deformable components; Coating the coated ibuprofen with a second coating material containing silicon dioxide; Applying mechanical stress to embed the second coating material on the first coating material of the coated ibuprofen; Sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises a first coating material that is not bound to the coated ibuprofen; Forming a pharmaceutical suspension containing twice-applied ibuprofen and a matrix solution or suspension; and Meter the pharmaceutical suspension into a mold; and The metered pharmaceutical suspension in the mold is freeze-dried to form a pharmaceutical composition.

如請求項38之醫藥組合物，其中該醫藥組合物包含50-400 mg伊布洛芬。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition comprises 50-400 mg ibuprofen.

如請求項38之醫藥組合物，其中該醫藥組合物包含65-85 % w/w伊布洛芬。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition comprises 65-85% w/w ibuprofen.

如請求項38之醫藥組合物，其中該醫藥組合物包含15-30 % w/w該等第一及第二塗覆材料。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition comprises 15-30% w/w of the first and second coating materials.

如請求項38之醫藥組合物，其中該第一塗覆材料經構形以掩蔽伊布洛芬之味道。The pharmaceutical composition of claim 38, wherein the first coating material is configured to mask the taste of ibuprofen.

如請求項38之醫藥組合物，其中該二氧化矽包含疏水性發煙二氧化矽。The pharmaceutical composition of claim 38, wherein the silica comprises hydrophobic fuming silica.

如請求項38之醫藥組合物，其中該基質溶液或懸浮液包含防通氣劑。The pharmaceutical composition of claim 38, wherein the base solution or suspension contains an anti-ventilating agent.

如請求項38之醫藥組合物，其中該醫藥組合物包含3-15 % w/w基質。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition comprises 3-15% w/w matrix.

如請求項38之醫藥組合物，其包含篩分未經塗覆之伊布洛芬。The pharmaceutical composition of claim 38, which comprises sieved uncoated ibuprofen.

如請求項38之醫藥組合物，其中篩分該經塗覆之伊布洛芬包含使該經塗覆之伊布洛芬通過包含兩個或更多個篩之裝置。The pharmaceutical composition of claim 38, wherein sieving the coated ibuprofen comprises passing the coated ibuprofen through a device comprising two or more screens.

如請求項38之醫藥組合物，其中篩分該經塗覆之伊布洛芬包含將該經塗覆之伊布洛芬篩分成75 µm或更大之平均粒度。The pharmaceutical composition of claim 38, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen into an average particle size of 75 µm or greater.

如請求項38之醫藥組合物，其中篩分該經塗覆之伊布洛芬包含將該經塗覆之伊布洛芬篩分成200 µm或更小之平均粒度。The pharmaceutical composition of claim 38, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen into an average particle size of 200 µm or less.

如請求項38之醫藥組合物，其中該第一塗覆材料包含蠟。The pharmaceutical composition of claim 38, wherein the first coating material comprises wax.

如請求項50之醫藥組合物，其中該蠟包含巴西棕櫚蠟、小燭樹蠟或合成蠟中之一或多者。The pharmaceutical composition of claim 50, wherein the wax comprises one or more of carnauba wax, candelilla wax or synthetic wax.

如請求項38之醫藥組合物，其中該基質溶液或懸浮液包含基質形成劑及結構形成劑。The pharmaceutical composition of claim 38, wherein the matrix solution or suspension comprises a matrix forming agent and a structure forming agent.

如請求項52之醫藥組合物，其中該基質形成劑包含水溶性材料、水可分散材料、多肽、多醣、聚乙烯醇、聚乙烯基吡咯啶酮及***樹膠中之一或多者。The pharmaceutical composition of claim 52, wherein the matrix forming agent comprises one or more of water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic.

如請求項52之醫藥組合物，其中該基質形成劑包含多肽。The pharmaceutical composition of claim 52, wherein the matrix forming agent comprises a polypeptide.

如請求項54之醫藥組合物，其中該多肽包含明膠。The pharmaceutical composition of claim 54, wherein the polypeptide comprises gelatin.

如請求項52之醫藥組合物，其中該結構形成劑包含甘露醇、右旋糖、乳糖、半乳糖及環糊精中之一或多者。The pharmaceutical composition of claim 52, wherein the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

如請求項52之醫藥組合物，其中該結構形成劑包含甘露醇。The pharmaceutical composition of claim 52, wherein the structure forming agent comprises mannitol.

如請求項38之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下包含4秒或更少之崩解時間達至少一個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition comprises a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有3秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項38之醫藥組合物，其中該醫藥組合物在5分鐘後具有10%或更少之溶解測試結果。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a dissolution test result of 10% or less after 5 minutes.

如請求項38之醫藥組合物，其中該醫藥組合物在5分鐘後具有5%或更少之溶解測試結果。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a dissolution test result of 5% or less after 5 minutes.

如請求項38之醫藥組合物，其中該醫藥組合物在5分鐘後具有3%或更少之溶解測試結果。The pharmaceutical composition of claim 38, wherein the pharmaceutical composition has a dissolution test result of 3% or less after 5 minutes.

如請求項38之醫藥組合物，其中該經計量之醫藥懸浮液之重量在目標重量之10%內。The pharmaceutical composition of claim 38, wherein the weight of the measured pharmaceutical suspension is within 10% of the target weight.

如請求項38之醫藥組合物，其中該經計量之醫藥懸浮液之重量在設定目標重量之5%內。The pharmaceutical composition of claim 38, wherein the weight of the measured pharmaceutical suspension is within 5% of the set target weight.

如請求項38之醫藥組合物，其中該基質溶液或懸浮液包含黏度調節劑。The pharmaceutical composition of claim 38, wherein the matrix solution or suspension contains a viscosity modifier.

如請求項76之醫藥組合物，其中該黏度調節劑包含黃原膠。The pharmaceutical composition of claim 76, wherein the viscosity modifier comprises xanthan gum.

如請求項38之醫藥組合物，其中將該經塗覆之伊布洛芬混合至基質溶液或懸浮液中包含在15-20℃下線上混合。The pharmaceutical composition of claim 38, wherein mixing the coated ibuprofen into the matrix solution or suspension comprises mixing on-line at 15-20°C.

如請求項44之醫藥組合物，其中該防通氣劑包含萜烯或萜品醇中之一或多者。The pharmaceutical composition of claim 44, wherein the anti-ventilation agent comprises one or more of terpene or terpineol.

如請求項44之醫藥組合物，其中該防通氣劑包含液體矯味劑。The pharmaceutical composition of claim 44, wherein the anti-ventilation agent comprises a liquid flavoring agent.

如請求項44之醫藥組合物，其中該防通氣劑包含含有檸檬烯之液體矯味劑。The pharmaceutical composition of claim 44, wherein the anti-ventilation agent comprises a liquid flavoring agent containing limonene.

如請求項44之醫藥組合物，其中該防通氣劑包含橙味矯味劑、檸檬味矯味劑、葡萄柚味矯味劑、酸檸檬味矯味劑、草莓味矯味劑或薄荷味矯味劑中之一或多者。The pharmaceutical composition of claim 44, wherein the anti-ventilation agent comprises one of an orange flavor corrective agent, a lemon flavor corrective agent, a grapefruit flavor corrective agent, a sour lemon flavor corrective agent, a strawberry flavor corrective agent or a mint flavor corrective agent or More.

如請求項44之醫藥組合物，其中該醫藥組合物包含1-5 % w/w防通氣劑。The pharmaceutical composition of claim 44, wherein the pharmaceutical composition comprises 1-5% w/w anti-ventilation agent.

如請求項38之醫藥組合物，其中該經塗覆之伊布洛芬在混合至該溶液基質中之後的前2個小時內經歷小於40%之粒度損失。The pharmaceutical composition of claim 38, wherein the coated ibuprofen undergoes a particle size loss of less than 40% in the first 2 hours after being mixed into the solution matrix.

如請求項38之醫藥組合物，其中該經塗覆之伊布洛芬在混合至該溶液基質中之後的前2個小時內經歷小於30%之粒度損失。The pharmaceutical composition of claim 38, wherein the coated ibuprofen undergoes a particle size loss of less than 30% in the first 2 hours after being mixed into the solution matrix.

如請求項38之醫藥組合物，其中該經塗覆之伊布洛芬在混合至該溶液基質中之後的前2個小時內經歷小於20%之粒度損失。The pharmaceutical composition of claim 38, wherein the coated ibuprofen undergoes a particle size loss of less than 20% in the first 2 hours after being mixed into the solution matrix.

一種治療患者之方法，其包含向患者投與如請求項38至86中任一項之醫藥組合物。A method of treating a patient, which comprises administering the pharmaceutical composition according to any one of claims 38 to 86 to the patient.

如請求項87之方法，其中該患者係人類。Such as the method of claim 87, wherein the patient is a human.

一種製備醫藥組合物之方法，其包含：用第一塗覆材料塗覆伊布洛芬以形成經塗覆之伊布洛芬，其中該第一塗覆材料包含一或多種可變形組分；對該經塗覆之伊布洛芬施加機械應力以使該一或多種可變形組分變形；用包含二氧化矽之第二塗覆材料塗覆該經塗覆之伊布洛芬；施加機械應力以將該第二塗覆材料包埋至該經塗覆之伊布洛芬之該第一塗覆材料上；篩分該經塗覆之伊布洛芬以去除過量第一塗覆材料，其中該過量第一塗覆材料包含未結合至該經塗覆之伊布洛芬之第一塗覆材料；形成包含兩次塗覆之伊布洛芬及基質溶液或懸浮液的醫藥懸浮液；及將該醫藥懸浮液計量至模具中；及冷凍乾燥該模具中之該經計量之醫藥懸浮液以形成醫藥組合物。A method for preparing a pharmaceutical composition, which comprises: Coating ibuprofen with a first coating material to form a coated ibuprofen, wherein the first coating material includes one or more deformable components; Applying mechanical stress to the coated ibuprofen to deform the one or more deformable components; Coating the coated ibuprofen with a second coating material containing silicon dioxide; Applying mechanical stress to embed the second coating material on the first coating material of the coated ibuprofen; Sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises a first coating material that is not bound to the coated ibuprofen; Forming a pharmaceutical suspension containing twice-applied ibuprofen and a matrix solution or suspension; and Meter the pharmaceutical suspension into a mold; and The metered pharmaceutical suspension in the mold is freeze-dried to form a pharmaceutical composition.

如請求項89之方法，其中該醫藥組合物包含50-400 mg伊布洛芬。The method of claim 89, wherein the pharmaceutical composition comprises 50-400 mg ibuprofen.

如請求項89之方法，其中該醫藥組合物包含65-85 % w/w伊布洛芬。The method of claim 89, wherein the pharmaceutical composition comprises 65-85% w/w ibuprofen.

如請求項89之方法，其中該醫藥組合物包含15-30 % w/w該等第一及第二塗覆材料。The method of claim 89, wherein the pharmaceutical composition comprises 15-30% w/w of the first and second coating materials.

如請求項89之方法，其中該醫藥組合物包含3-15 % w/w基質。The method of claim 89, wherein the pharmaceutical composition comprises 3-15% w/w matrix.

如請求項89之方法，其包含篩分未經塗覆之伊布洛芬。The method of claim 89, which comprises sieving uncoated ibuprofen.

如請求項89之方法，其中該第一塗覆材料經構形以掩蔽該伊布洛芬之味道。The method of claim 89, wherein the first coating material is configured to mask the taste of the ibuprofen.

如請求項89之方法，其包含將該懸浮液計量至預成型模具中。The method of claim 89, which comprises metering the suspension into a preforming mold.

如請求項89之方法，其中該二氧化矽包含疏水性發煙二氧化矽。The method of claim 89, wherein the silica comprises hydrophobic fuming silica.

如請求項89之方法，其中篩分該經塗覆之伊布洛芬包含使該經塗覆之伊布洛芬通過包含兩個或更多個篩之裝置。The method of claim 89, wherein sieving the coated ibuprofen comprises passing the coated ibuprofen through a device comprising two or more screens.

如請求項89之方法，其中篩分該經塗覆之伊布洛芬包含將該經塗覆之伊布洛芬篩分成75 µm或更大之平均粒度。The method of claim 89, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen into an average particle size of 75 µm or greater.

如請求項89之方法，其中篩分該經塗覆之伊布洛芬包含將該經塗覆之伊布洛芬篩分成200 µm或更小之平均粒度。The method of claim 89, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen into an average particle size of 200 µm or less.

如請求項89之方法，其中該第一塗覆材料包含蠟。The method of claim 89, wherein the first coating material comprises wax.

如請求項89之方法，其中該第一塗覆材料包含巴西棕櫚蠟、小燭樹蠟或合成蠟中之一或多者。The method of claim 89, wherein the first coating material comprises one or more of carnauba wax, candelilla wax or synthetic wax.

如請求項89之方法，其中該基質溶液或懸浮液包含基質形成劑及結構形成劑。The method of claim 89, wherein the matrix solution or suspension comprises a matrix forming agent and a structure forming agent.

如請求項103之方法，其中該基質形成劑包含水溶性材料、水可分散材料、多肽、多醣、聚乙烯醇、聚乙烯基吡咯啶酮及***樹膠中之一或多者。The method of claim 103, wherein the matrix forming agent comprises one or more of water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic.

如請求項103之方法，其中該基質形成劑包含多肽。The method of claim 103, wherein the matrix forming agent comprises a polypeptide.

如請求項105之方法，其中該多肽包含明膠。The method of claim 105, wherein the polypeptide comprises gelatin.

如請求項103之方法，其中該結構形成劑包含甘露醇、右旋糖、乳糖、半乳糖及環糊精中之一或多者。The method of claim 103, wherein the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

如請求項103之方法，其中該結構形成劑包含甘露醇。The method of claim 103, wherein the structure forming agent comprises mannitol.

如請求項89之方法，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有3秒或更少之崩解時間達至少兩個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少兩個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少三個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25° C. and at least 60% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少30℃及至少65%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少40℃及至少75%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少六個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity.

如請求項89之方法，其中該醫藥組合物在至少25℃及至少60%相對濕度之儲存條件下具有4秒或更少之崩解時間達至少一個月。The method of claim 89, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity.

如請求項89之方法，其中該基質溶液或懸浮液包含防通氣劑。The method of claim 89, wherein the matrix solution or suspension contains an anti-ventilation agent.

如請求項89之方法，其中該醫藥組合物在5分鐘後具有10%或更少之溶解測試結果。The method of claim 89, wherein the pharmaceutical composition has a dissolution test result of 10% or less after 5 minutes.

如請求項89之方法，其中該醫藥組合物在5分鐘後具有5%或更少之溶解測試結果。The method of claim 89, wherein the pharmaceutical composition has a dissolution test result of 5% or less after 5 minutes.

如請求項89之方法，其中該醫藥組合物在5分鐘後具有3%或更少之溶解測試結果。The method of claim 89, wherein the pharmaceutical composition has a dissolution test result of 3% or less after 5 minutes.

如請求項89之方法，其中該經計量之醫藥懸浮液之重量在目標重量之10%內。The method of claim 89, wherein the weight of the measured pharmaceutical suspension is within 10% of the target weight.

如請求項89之方法，其中該經計量之醫藥懸浮液之重量在目標重量之5%內。The method of claim 89, wherein the weight of the measured pharmaceutical suspension is within 5% of the target weight.

如請求項89之方法，其中該基質溶液或懸浮液包含黏度調節劑。The method of claim 89, wherein the matrix solution or suspension contains a viscosity modifier.

如請求項128之方法，其中該黏度調節劑包含黃原膠。The method of claim 128, wherein the viscosity modifier comprises xanthan gum.

如請求項89之方法，其中將該經塗覆之伊布洛芬混合至基質溶液或懸浮液中包含在15-20℃下線上混合。The method of claim 89, wherein mixing the coated ibuprofen into the matrix solution or suspension comprises in-line mixing at 15-20°C.

如請求項122之方法，其中該防通氣劑包含萜烯或萜品醇中之一或多者。The method of claim 122, wherein the anti-ventilation agent comprises one or more of terpene or terpineol.

如請求項122之方法，其中該防通氣劑包含液體矯味劑。The method of claim 122, wherein the anti-ventilation agent comprises a liquid flavoring agent.

如請求項122之方法，其中該防通氣劑包含含有檸檬烯之液體矯味劑。The method of claim 122, wherein the anti-ventilation agent comprises a liquid flavoring agent containing limonene.

如請求項122之方法，其中該防通氣劑包含橙味矯味劑、檸檬味矯味劑、葡萄柚味矯味劑、酸檸檬味矯味劑、草莓味矯味劑或薄荷味矯味劑中之一或多者。The method of claim 122, wherein the anti-ventilation agent comprises one or more of orange flavor, lemon flavor, grapefruit flavor, sour lemon flavor, strawberry flavor, or mint flavor. .

如請求項89之方法，其中該醫藥組合物包含3-10 % w/w基質形成劑。The method of claim 89, wherein the pharmaceutical composition comprises 3-10% w/w matrix forming agent.

如請求項89之方法，其中該醫藥組合物包含3-10 % w/w結構形成劑。The method of claim 89, wherein the pharmaceutical composition comprises 3-10% w/w structure forming agent.

如請求項89之方法，其中該經塗覆之伊布洛芬在混合至該溶液基質中之後的前2個小時內經歷小於40%之粒度損失。The method of claim 89, wherein the coated ibuprofen undergoes a particle size loss of less than 40% in the first 2 hours after being mixed into the solution matrix.

如請求項89之方法，其中該經塗覆之伊布洛芬在混合至該溶液基質中之後的前2個小時內經歷小於30%之粒度損失。The method of claim 89, wherein the coated ibuprofen undergoes a particle size loss of less than 30% in the first 2 hours after being mixed into the solution matrix.

如請求項89之方法，其中該經塗覆之伊布洛芬在混合至該溶液基質中之後的前2個小時內經歷小於20%之粒度損失。The method of claim 89, wherein the coated ibuprofen undergoes a particle size loss of less than 20% in the first 2 hours after being mixed into the solution matrix.